The DOI matches its Crossref record; 40 of the 42 references it cites were found in a registry or an index; 42 of the 61 sources its claims cite were checked for support.
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
Open accessAbstract
E3 ubiquitin ligase. We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface. Computational zinc finger docking and biochemical analysis predict that more than 150 zinc fingers bind the drug-CRBN complex in vitro, and we show that selective zinc finger degradation can be achieved through compound modifications. Our results provide a rationale for therapeutically targeting transcription factors that were previously considered undruggable.
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Claims the paper makes
58 Own result · 25 Own interpretation · 14 Partly supported · 8 No full text of the sources · 8 Own method · 5 No basis given · 1 Supported · 1 Supported so far · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Previous work has implicated the second C2H2 ZF domain in IKZF1 and IKZF3 (5, 7), and ZF4 of ZFP91 as the drug-inducible degrons (5, 7, 16).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
- Not checked — no full text of the sourcecites [5] source
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
The “CRBN functions as a DCAF for the CRL4CRBN ligase” section (page unavailable) reports drug-induced degradation of IKZF1 and IKZF3. It does not identify their second C2H2 zinc finger as a degron, and the searched passages do not address ZFP91 or its ZF4 domain. (LLM, conf=0.83)
- Supportedcites [16] source
The Discussion identifies a common structural motif in ZFP91 ZnF4 and IKZF1/3 ZnF2 that mediates interaction with the CRBN–IMiD complex. The ZFP91 substrate section also reports that disrupting ZnF4 largely disrupts drug-induced binding, supporting the cautious wording “implicated” as drug-inducible degrons. (LLM, conf=0.92)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“proteome-wide mass-spectrometry demonstrated selective degradation of endogenous IKZF1/3, and ZFP91 in multiple cell lines (3, 4, 16).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
- Partly supportedcites [3] sourceExperimental — accuracy not yet measured
The copy’s Abstract (page not provided) reports SILAC-based mass spectrometry showing reduced IKZF1 and IKZF3 abundance in the MM1S cell line. It separately reports decreased endogenous IKZF1 and IKZF3 in cell lines, but does not report proteome-wide mass spectrometry across multiple cell lines or degradation of ZFP91. (LLM, conf=0.88)
- Partly supportedcites [4] sourceExperimental — accuracy not yet measured
The Results section reports global mass-spectrometry profiling in KG-1 cells, and Extended Data Table 1 shows reduced IKZF1 and ZFP91 protein abundance after lenalidomide treatment. Extended Data Figure 8 also describes proteomic measurement of IKZF1 in MDS-L cells. The copy does not show mass-spectrometric degradation of endogenous IKZF3 or establish degradation of all three proteins across multiple cell lines; its IKZF3 assay used a luciferase reporter. (LLM, conf=0.87)
- Partly supportedcites [16] sourceExperimental — accuracy not yet measured
The ‘Identification of novel CRL4 CRBN targets through pSILAC MS’ section reports mass-spectrometry detection of altered ZFP91 turnover in HEK293T and Hct116 cells, and the ‘ZFP91 is a lenalidomide-dependent CRL4 CRBN substrate’ section confirms its degradation in additional cell lines. The paper describes IKZF1/3 degradation as an established finding, but says its own proteomics experiments used non-hematopoietic cells to look beyond IKZF1/3; it does not show proteome-wide mass-spectrometry detection of their degradation across multiple cell lines. (LLM, conf=0.85)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Thalidomide and its derivatives, lenalidomide and pomalidomide, are effective therapies for the hematologic malignancies multiple myeloma, del(5q) myelodysplastic syndrome, and mantle cell lymphoma (1).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
- Partly supportedcites [1] sourceExperimental — accuracy not yet measured
The Introduction states that lenalidomide is highly effective for multiple myeloma, mantle cell lymphoma, and del(5q) myelodysplastic syndrome. It identifies thalidomide and pomalidomide as related drugs in widespread clinical use, but does not establish that each is an effective treatment for all three diseases. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys2-His2 (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Abstract
What the sources say
- Partly supportedcites [2] sourceExperimental — accuracy not yet measured
The indexed passages describing Figs. 1 and 3 (section labeled Abstract; page unavailable) report lenalidomide-dependent binding of IKZF1 and IKZF3 to cereblon, IKZF1 ubiquitylation, and proteasome-dependent loss of both proteins; the Fig. 1 passage also reports similar down-regulation with pomalidomide. The copy does not establish that thalidomide causes their degradation, or specifically identify the recruited region as a C2H2 zinc finger domain. It describes cereblon as a substrate-recognition component of a cullin-dependent ligase but does not give the CRL4CRBN designation. (LLM, conf=0.88)
- Partly supportedcites [3] sourceExperimental — accuracy not yet measured
The indexed text (section labelled Abstract; page unavailable) shows that lenalidomide recruits IKZF1 and IKZF3 to CRBN through a region within zinc finger domain 2, promoting their ubiquitination and degradation. It also reports that thalidomide and pomalidomide decrease both proteins’ abundance, but does not establish that those two drugs use the same zinc-finger recruitment and ubiquitination mechanism. (LLM, conf=0.87)
- Partly supportedcites [4] sourceExperimental — accuracy not yet measured
The Discussion and Differential substrate specificity sections (pages not provided) state that all three drugs induce CRL4CRBN-mediated ubiquitination and degradation of IKZF1 and IKZF3. The copy mentions an IKZF1/3 degron but does not identify it as a C2H2 zinc finger domain or explicitly describe the degradation of these proteins as proteasomal. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [5] source
- Not checked — no full text of the sourcecites [6] source
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
The 'CRBN functions as a DCAF' section identifies CRBN as a substrate receptor and reports IMiD-dependent degradation of IKZF1/3, noting that thalidomide is less efficient than lenalidomide and pomalidomide. The 'Thalidomide is an agonist and antagonist' section proposes recruitment of Ikaros to IMiD-bound CRBN but says the detailed binding mode remains to be established. Our copy does not identify a C2H2 zinc finger domain as the recruited portion, so that specific mechanism is unsupported. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Given the CRL4CRBN protein architecture and its ~100 Å ubiquitination radius (6, 7, 22)”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
What the sources say
- Not checked — no full text of the sourcecites [6] source
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
In “CRBN functions as a DCAF for the CRL4CRBN ligase” (page unavailable), the paper describes a ubiquitination zone created by rotation of the ligase arm. It gives the zone’s dimensions as up to 340 × 110 × 30 Å, not a ubiquitination radius of approximately 100 Å. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [22] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Thalidomide, lenalidomide and pomalidomide mediate CRL4CRBN-dependent degradation of a larger number of proteins than previously appreciated through a C2H2 ZF degron (3, 4, 16).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
What the sources say
- Partly supportedcites [3] sourceExperimental — accuracy not yet measured
The paper reports CRL4–CRBN-dependent degradation of IKZF1 and IKZF3 by lenalidomide, and says thalidomide and pomalidomide also decreased their abundance (Abstract; page unavailable). It identifies a degradation-determining sequence within an IKZF3 zinc-finger domain, but does not establish the claimed broader set of proteins degraded by all three drugs through a C2H2 zinc-finger degron. (LLM, conf=0.84)
- Partly supportedcites [4] sourceExperimental — accuracy not yet measured
The Discussion and Differential substrate specificity sections report CRL4CRBN-mediated degradation of IKZF1 and IKZF3 by all three drugs and identify CK1α as an additional substrate strongly affected by lenalidomide, but not thalidomide. The CK1α is a substrate of CRL4CRBN section says its responsive region has no evident homology to the previously identified IKZF1/3 degron. The paper therefore does not support the claim that the expanded set of proteins is degraded through a C2H2 zinc-finger degron. (LLM, conf=0.88)
- Partly supportedcites [16] sourceExperimental — accuracy not yet measured
The ‘ZFP91 is a lenalidomide-dependent CRL4 CRBN substrate’ section (page not provided) reports degradation of the additional substrate ZFP91 with lenalidomide and pomalidomide, but says thalidomide’s effect in cells was minimal. The paper proposes a common zinc-finger motif for IMiD-dependent binding; it does not establish degradation of a larger set of proteins by all three drugs through a C2H2 degron. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Examination of published proteome-wide mass spectrometry data confirmed degradation of endogenous, full-length WIZ in WSU-DLCL2 (human diffuse large B cell lymphoma) and TMD8 (human diffuse large B cell lymphoma) cells in the presence of lenalidomide and the thalidomide analog CC-122 (fig. S7C) (20).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > In silico identification of novel ZFs that interact with the drug-CRBN interface
What the sources say
- Supportedcites [20] source
The ‘Differential activities of CC-122 and lenalidomide in DLBCL’ section describes mass-spectrometry proteomics of TMD8 and WSU-DLCL2 cells treated with both drugs. The citation identifies the published data that the citing authors examined; the WIZ finding is attributed to their examination, not to a finding reported in the source paper (page unavailable in our copy). (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“and could contribute to developmental abnormalities in fetuses exposed to thalidomide (25–30).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
What the sources say
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
The Introduction (page not provided) links HIC1 haploinsufficiency to Miller–Dieker syndrome, supporting a possible connection between HIC1 and developmental abnormalities. It does not address thalidomide exposure or the proposed roles of HIC2, GZF1, OSR1, OSR2, and SALL4 in exposed fetuses. (LLM, conf=0.82)
- Partly supportedcites [26] sourceExperimental — accuracy not yet measured
The Hic2 Has a Haploinsufficient Cardiovascular Phenotype section (page unavailable) reports developmental delay and cardiac defects in Hic2-mutant mouse embryos, supporting a developmental role for HIC2. The paper does not address thalidomide exposure or establish that HIC2 contributes to abnormalities in exposed fetuses; it also does not establish the proposed roles of GZF1, OSR1, OSR2, or SALL4. (LLM, conf=0.86)
- Partly supportedcites [27] sourceExperimental — accuracy not yet measured
The section “Osr1 regulates embryonic myogenesis” (page not provided) reports limb muscle patterning defects in Osr1-deficient mouse embryos, supporting a developmental role for OSR1. It does not link those defects to thalidomide exposure or address the proposed contribution of HIC1, HIC2, GZF1, OSR2, and SALL4; searches for thalidomide and the gene list found no such passage. (LLM, conf=0.82)
- Partly supportedcites [28] sourceExperimental — accuracy not yet measured
The Results and in situ hybridization passages (page unavailable) show Osr2 expression in developing mouse limbs and craniofacial tissues, providing developmental context for one gene in the claim. They do not link Osr2 to thalidomide exposure or fetal abnormalities, and this paper does not address HIC1, HIC2, GZF1, or SALL4. (LLM, conf=0.78)
- Partly supportedcites [29] sourceExperimental — accuracy not yet measured
The section on GZF1 and the HOXA10 regulatory region proposes a possible role for GZF1 in normal kidney development. It does not address thalidomide exposure or fetal abnormalities, and it does not implicate the other five named genes in those abnormalities. (LLM, conf=0.82)
- Partly supportedcites [30] sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) supports SALL4 as a cause of developmental abnormalities in a family previously thought to have thalidomide embryopathy. It does not address HIC1, HIC2, GZF1, OSR1, or OSR2. It also argues that the family's phenotype was likely misdiagnosed as thalidomide embryopathy, rather than showing that these genes contribute to abnormalities caused by thalidomide exposure. (LLM, conf=0.86)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Several of the ZFs identified as degraded in functional experiments, or in vitro binders that could be targeted with further drug development, have been implicated in human disease.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
What the sources say
- Not checked — no full text of the sourcecites [23] source
- Not checked — no full text of the sourcecites [24] source
- Supportedcites [25] source
The Introduction identifies HIC1 as a zinc-finger transcription factor and links it to human tumors and Miller–Dieker syndrome. This supports the paper's use as an example of a disease-implicated zinc-finger protein; the degradation experiments and potential drug development are the citing authors' framing, not findings attributed to this source. (LLM, conf=0.87)
- Supportedcites [26] source
The Results section reports that loss of HIC2 is associated with congenital cardiac disease in distal 22q11 deletion syndrome. The Discussion identifies HIC2 as a contributor to the syndrome’s phenotype, supporting its use as an example of a disease-implicated protein. (LLM, conf=0.85)
- Could not verifycites [27] sourceExperimental — accuracy not yet measured
The References section identifies Osr1 and Osr2 as zinc-finger transcription factors, while the experimental sections concern Osr1’s role in embryonic limb development. Searches for degraded zinc-finger proteins, in vitro binders, drug development, and their implication in human disease found no passage addressing the attributed claim. Page numbers were not available in our copy. (LLM, conf=0.75)
- Could not verifycites [28] sourceExperimental — accuracy not yet measured
The Results section identifies mouse OSR2 as a zinc-finger protein, and §2.1 identifies a putative human OSR2 gene. Neither passage links any zinc-finger protein to human disease; searches for disease implications, experimental degradation, in vitro binding, and drug development found no such discussion in our copy. Page numbers were not available. (LLM, conf=0.76)
- Could not verifycites [29] sourceExperimental — accuracy not yet measured
The analysis of GZF1 zinc finger motifs reports DNA-binding experiments, but does not link GZF1 or several zinc finger proteins to human disease. A search for “human disease” found that phrase only in a reference about GDNF/RET signaling, not in a finding about the zinc finger proteins described in the claim. The copy also does not address their degradation or potential drug targeting. (LLM, conf=0.76)
- Supportedcites [30] source
The Figure 3 caption identifies zinc-finger motifs in SALL4, and the Discussion states that SALL4 mutations cause a range of clinical phenotypes. This supports SALL4 as an example of a zinc-finger protein implicated in human disease; the citing paper’s degradation and drug-development framing is not a finding attributed to this source. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Replacing ZF3 with ZF1 in the context of the ZF2-ZF3 construct (ZF2-ZF1) decreased the binding affinity by a factor of 6 (Ki 1027±302 nM).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > A C2H2 ZF library screen identifies novel degrons and protein targets
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 16
- It may state two separate claims as one. 41
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Transcription factors have remained challenging drug targets due to the absence of druggable active sites (14).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
- Partly supportedcites [14] sourceExperimental — accuracy not yet measured
In the section on key undruggable cancer targets (pages unavailable), Reddy says transcription factors are difficult to inhibit, while Soucek describes the difficulty of targeting proteins without a defined, sufficient drug-binding surface and includes transcription factors among them. The paper does not specifically say that transcription factors lack druggable active sites; it also identifies intracellular localization and interactions with many cofactors as reasons they are difficult to target. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“IKZF1 and IKZF3 belong to the family of Cys2-His2 (C2H2) zinc finger (ZF) proteins (11).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
- Partly supportedcites [11] sourceExperimental — accuracy not yet measured
The section ‘Amino- and carboxy-terminal zinc finger domains are required for pericentromeric targeting’ (page not provided) describes Ikaros as having C2H2 zinc fingers, supporting that part of the claim. Our copy does not establish that IKZF3 also belongs to the C2H2 zinc finger protein family; a search for Aiolos found it only in a reference title. (LLM, conf=0.85)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“E3 ubiquitin ligases recognize their substrates through degrons, short stretches of primary sequence that are necessary and sufficient for the interaction with substrate receptors of ubiquitin ligases (15).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
- Partly supportedcites [15] sourceExperimental — accuracy not yet measured
The Results section, “Primary degrons specify substrate recognition by E3 ligases” (page unavailable), says E3 ligases bind substrates through short primary degron motifs. But “The underappreciated complexity of the degrome” explicitly cautions that not all E3 ligases bind peptide degrons, and the paper does not establish that a short sequence is necessary and sufficient for interaction with substrate receptors generally. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“CK1α is essential for the survival of hematopoietic stem cells, and heterozygous deletion of its gene in del(5q) myelodysplastic syndrome provides a therapeutic window for eliminating the malignant stem cell clone (10).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
- Partly supportedcites [10] sourceExperimental — accuracy not yet measured
The Results section, “Csnk1a1 is required for adult murine hematopoiesis” (page unavailable), reports that complete Csnk1a1 deletion sharply reduced hematopoietic stem cells, indicating a requirement for their survival. The Discussion and the Results section on CK1 inhibition describe a therapeutic window for targeting del(5q) haploinsufficient cells, but the experiments show selective loss of viability in cultured cells, not elimination of the malignant stem cell clone. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Thalidomide analogs bind Cereblon (CRBN), the substrate receptor of the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase and alter its substrate selectivity to recruit, ubiquitinate and degrade seemingly unrelated proteins including Ikaros (IKZF1), Aiolos (IKZF3), Casein kinase 1 alpha (CK1α) and GSPT1 (2–7).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
- Partly supportedcites [2] sourceExperimental — accuracy not yet measured
The indexed passage labeled Abstract (page unavailable) reports that lenalidomide promotes cereblon binding to IKZF1 and IKZF3, ubiquitylation of IKZF1, and cereblon-dependent degradation of both proteins. It also discusses altered cereblon substrate specificity, but the passages do not establish CK1α or GSPT1 as substrates. Thus this paper supports the IKZF1/IKZF3 portion of the multi-citation sentence, not the full list attributed to it. (LLM, conf=0.88)
- Partly supportedcites [3] sourceExperimental — accuracy not yet measured
The paper’s Abstract reports that lenalidomide binds the CRBN-containing ligase complex and promotes recruitment, ubiquitination, and degradation of IKZF1 and IKZF3. It does not identify CK1α or GSPT1 as targets, so it supports only part of the cited sentence. (LLM, conf=0.90)
- Partly supportedcites [4] sourceExperimental — accuracy not yet measured
The CK1α-substrate and Differential substrate specificity sections (page unavailable) show that CRBN-binding thalidomide analogs can alter substrate selection: the paper reports degradation of IKZF1 and IKZF3 and demonstrates lenalidomide-dependent recruitment, ubiquitination, and degradation of CK1α. It also shows that the analogs differ in which substrates they affect. Our copy does not identify GSPT1 as a substrate (searched: GSPT1 and translation termination factor), so it does not support the full list. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [5] source
- Not checked — no full text of the sourcecites [6] source
- Partly supportedcites [7] sourceExperimental — accuracy not yet measured
The sections on IMiD binding and CRBN ligase function describe thalidomide analogs binding CRBN and promoting the targeting of IKZF1 and IKZF3 for degradation, with thalidomide less effective than lenalidomide and pomalidomide. The paper also describes a change in substrate recruitment, but the passages do not support the claim that CK1α or GSPT1 is recruited, ubiquitinated, or degraded. No page numbers are available in our copy. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“HIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 have all been implicated in development”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
What the sources say
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
The Introduction (page not provided) links HIC1 to Miller–Dieker syndrome, supporting its implication in development. The paper does not address developmental roles for HIC2, GZF1, OSR1, OSR2, or SALL4, so it does not support the claim about all six genes. (LLM, conf=0.84)
- Partly supportedcites [26] sourceExperimental — accuracy not yet measured
The introduction describes developmental defects in mice lacking Hic1 and a role for Hic2 in embryonic cardiovascular development; the cardiac-development results further support Hic2’s role. The cited paper does not establish the claim for GZF1, OSR1, OSR2, or SALL4 (searched those gene names and developmental roles). (LLM, conf=0.88)
- Partly supportedcites [27] sourceExperimental — accuracy not yet measured
The Results and the section “Osr1 maintains muscle connective tissue identity” (page unavailable) connect OSR1 to embryonic limb development and discuss a developmental finding in Osr1/Osr2 double mutants. Searches for HIC1, HIC2, GZF1, and SALL4 found no passages implicating those four genes in development, so the source supports only part of the six-gene claim. (LLM, conf=0.89)
- Partly supportedcites [28] sourceExperimental — accuracy not yet measured
The Results and Figure 2 describe OSR1 and OSR2 expression in developing mouse tissues, supporting their association with development. The paper does not address HIC1, HIC2, GZF1, or SALL4, so it does not support the full list. (LLM, conf=0.88)
- Partly supportedcites [29] sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) links GZF1 to renal branching morphogenesis, and the discussion of GZF1 and HOXA10 (page unavailable) considers a possible role in kidney development. The paper does not establish a developmental role for HIC1, HIC2, OSR1, OSR2, or SALL4; HIC1 appears only in references concerning transcriptional repression. (LLM, conf=0.88)
- Partly supportedcites [30] sourceExperimental — accuracy not yet measured
The introduction and Discussion link SALL4 mutations to congenital limb and other malformations, supporting its implication in development. The paper does not address HIC1, HIC2, GZF1, OSR1, or OSR2, so it does not support the claim about all six genes (searched for those gene names). (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The majority of E3 ligase degrons are characterized by conserved primary sequence motifs that lie in unstructured regions of the protein substrate (15).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
What the sources say
- Partly supportedcites [15] sourceExperimental — accuracy not yet measured
The Results section, “Primary degrons specify substrate recognition by E3 ligases,” reports that catalogued primary degrons are significantly sequence-conserved and tend to lie in intrinsically disordered regions. But “The underappreciated complexity of the degrome” says it is not yet clear what fraction of E3 ligases recognize peptide degrons. The paper therefore supports the description of known primary degrons, not the claim that a majority of E3 ligase degrons have these features. (LLM, conf=0.87)
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- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sequence alignment of the C2H2 ZF hits (Fig. 3A) highlighted shared residues that are part of the PROSITE C2H2 ZF search motif (IKZF3 C148, C151, H164, H168, F155), residues that stabilize the ternary fold of the ZF domain (IKZF3 L161), and residues that frequently appear within C2H2 ZF domains (IKZF3 G152).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Identification of amino acid loci critical to degradation
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In the paper
“Deletion of ZF2 (aa 146–168) in full–length IKZF3 rendered the reporter resistant to drug treatment, whereas deletion of the other ZFs had little or no effect (fig. S1C).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > A C2H2 ZF library screen identifies novel degrons and protein targets
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In the paper
“Accordingly, IKZF3 ZF2 (aa 146–168), which is identical to IKZF1 ZF2 (aa 145–167; fig. S1D), was sufficient to confer CRBN-dependent degradation of the reporter (Fig. 1C).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > A C2H2 ZF library screen identifies novel degrons and protein targets
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In the paper
“Unlike previous CRBN structures, CRBN bound IKZF1 ZF2 in an ‘open’ conformation, with its N- and C-terminal domains separated and stabilized by crystal contacts (Fig. 4A and fig. S4A).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
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In the paper
“Mutation of these two residues impaired degradation in validation experiments, whereas N149, a residue that was not highlighted in the mutagenesis screen, tolerated mutation (Fig. 3D).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Identification of amino acid loci critical to degradation
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In the paper
“IKZF1 ZF2 (amino acid residues (aa) 141–174) was the shortest construct that showed binding to CRBN-pomalidomide, with a Ki of 2314 ±81 nM.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > A C2H2 ZF library screen identifies novel degrons and protein targets
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In the paper
“In addition, the screen highlighted two non-structural residues (IKZF3 Q147 and A153) that varied among the other ZF degrons (Fig. 3A), but were important for degradation of the IKZF3 ZF2 reporter (Fig. 3, B and C).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Identification of amino acid loci critical to degradation
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In the paper
“All 6 ZFs that mediated degradation of their full-length protein carry an additional ZF C-terminal to the one identified in the library screen, whereas 5 of 6 ZFs that did not mediate degradation of their corresponding full-length protein do not posses a proximal C-terminal ZF.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > A C2H2 ZF library screen identifies novel degrons and protein targets
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In the paper
“but only C-x(2)-C ZFs were found destabilized in the screen (Fig. 3A).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Identification of amino acid loci critical to degradation
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In the paper
“While ZNF692 ZF4 and IKZF1 ZF2 show similar binding modes (Fig. 4C), the position of ZNF692 ZF4 is offset with respect to IKZF1 ZF2 (Fig. 4E and fig. S4, G and H), without significant differences in binding affinity (fig. S4I).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Of the 16 ZFs, WIZ ZF7 showed partial degradation in the presence of pomalidomide, the best in vitro binder in the set (fig. S6E and fig. S7, A and B).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > In silico identification of novel ZFs that interact with the drug-CRBN interface
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thalidomide lacks the C4 amino group (Fig. 5B) and mutation of IKZF1 Q146 (IKZF3 Q147) to isoleucine, which removes the ability to form a hydrogen bond with the drug, equalizes the binding affinity of IKZF1 ZF2-ZF3 to CRBN across the three compounds accordingly (Fig. 5C and fig. S5, B and C).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, introducing a single residue mutation at the drug-ZF interface of IKZF3, Q147 to a glutamic acid residue, stabilized the IKZF3 reporter (IKZF3 ZF2 Q147E; Fig. 3D), whereas an equivalent glutamic acid allows robust reporter degradation in the sequence context of E4F1 (Fig. 3A and fig. S2A).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > ZF degrons show epistatic properties during CRL4CRBN engagement
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both IKZF1 ZF2 and ZNF692 ZF4 bind a complementary groove on the CRBN C-terminal domain (Fig. 4C), interact with the compound through their β-hairpin loops, and match the overall backbone conformation of previous models of the ZF-drug-CRBN complex (fig. S4E).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IKZF1 ZF2 N148 and Q149 (IKZF3 N149 and Q150; fig. S1D) form hydrophobic interactions through their amphipathic side chains with CRBN residues H353 and Y355 (Fig. 4D), explaining CRBN compatibility with diverse amino acids at these ZF positions.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
plaindirect- Asserted: passes — The authors put it forward as true.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In each structure, the β-hairpin glycine of the ZF packs against the phthalimide ring of pomalidomide similar to the β-hairpins of CK1α (6) and GSPT1 (5), affirming the structural importance of a glycine residue at this position (Fig. 4D and fig. S4F).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mutation of R185 to alanine, or replacement of all three arginines with the corresponding amino acids in ZF1 (IGP) reduced the affinity of the ZF2-ZF3 construct similar to that of ZF2-ZF1 (Fig. 1A) or ZF2 alone as predicted by our model (fig. S4D).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The IKZF1 Q146 side chain (IKZF3 Q147) packs against the phthalimide group of pomalidomide and forms a water-mediated hydrogen bond with the C4 amino group of the compound (Fig. 5, A and B and fig. S5A).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Analogously, IKZF1 ZF1, a ZF that was not predicted to bind CRBN in silico (Fig. 6A), did not bind CRBN in vitro (fig. S6C).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > In silico identification of novel ZFs that interact with the drug-CRBN interface
plainSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The modified thalidomide analogs induced mild but significant degradation for some of these ZFs, including 2 ZFs destabilized by CC-122 (WIZ ZF6, BCL6 ZF3), 2 by CC-220 (BCL6B ZF2, HIC2 ZF5), and 8 by CC-885 (BCL6 ZF3, BCL6B ZF2, OSR1 ZF1, ZBTB7B ZF2, SALL3 ZF4, SALL4 ZF2, ERG1 ZF3, SALL1 ZF4).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Different thalidomide analogs target distinct sets of ZFs for degradation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“IKZF1 Q146 forms the only side chain interaction with the compound (Fig. 5A), and mutation of the equivalent residue in IKZF3 (Q147) stabilized the reporter in the saturation mutagenesis experiment (Fig. 3, B and D).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This amino acid change decreases binding to CRBN-pomalidomide in vitro by a factor 2–3 (fig. S5B), and stabilizes the respective ZF reporter in cells (Fig. 5D).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Different thalidomide analogs target distinct sets of ZFs for degradation
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Most strikingly, IKZF2 ZF2 is not degraded by pomalidomide, lenalidomide, or CC-122, but is efficiently degraded by CC-220.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
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In the paper
“Together, these results establish IKZF1/IKZF3 ZF2 as the minimal unit required for thalidomide analog-induced CRBN binding in vitro and for CRL4CRBN-dependent degradation in cells.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > A C2H2 ZF library screen identifies novel degrons and protein targets
direct- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As supported by the ZNF692 structure, release of the C-terminal domain is not required for ZF binding (Fig. 4B).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
plainSingle case- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results are consistent with our findings that while IKZF1/IKZF3 ZF2 constitutes the minimal ZF degron using the degradation reporter, an IKZF1 construct spanning ZF2 and ZF3 conferred higher affinity binding to CRBN-pomalidomide than ZF2 alone in vitro (Fig. 1A).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > A C2H2 ZF library screen identifies novel degrons and protein targets
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Because amino acids in the α-helical portion of some ZF domains recognize DNA base-pairs in a sequence-specific manner (12)”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
- Not checked — no full text of the sourcecites [12] source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“IKZF1 and IKZF3 are lymphocyte lineage transcription factors (8, 9) that are essential for the survival of the malignant plasma cells in multiple myeloma.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
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In the paper
“the approximately 800 C2H2 ZF proteins are predicted to comprise the largest group of transcription factors in the human genome (13).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Introduction
What the sources say
- Not checked — no full text of the sourcecites [13] source
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“ZNF827 is reported to be an essential scaffolding protein for alternative lengthening of telomeres (ALT) (24)”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
What the sources say
- Not checked — no full text of the sourcecites [24] source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“ZFP91 is implicated in NF-κB signaling (23)”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
What the sources say
- Not checked — no full text of the sourcecites [23] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we expect degradation of full-length ZF proteins to be less dependent on lysine accessibility, and instead primarily determined by the protein synthesis rate and the affinity/binding kinetics of the internal ZF degron to CRBN, which can be modulated by the drug.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ZF degrons are thus defined by the sequence context of their amino acid side chains that contact the drug-CRBN interface (Fig. 4D), which suggests an epistatic relationship of these variable ZF residues during CRL4CRBN engagement and explains the absence of a primary sequence consensus.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > ZF degrons show epistatic properties during CRL4CRBN engagement
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Recruitment and degradation are thus influenced by the complementarity of the substrate to the drug-CRBN binding groove and the sequence context of the contacting ZF residues, making the overall “shape” of the ZF the important binding determinant, rather than its primary sequence.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results demonstrate that thalidomide analogs with chemical alterations at the drug-ZF interface promote degradation of distinct sets of ZFs and are capable of converting ZFs that bind CRBN-pomalidomide weakly in vitro into degraded ZFs in cells.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Different thalidomide analogs target distinct sets of ZFs for degradation
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As the majority of these ZFs are recruited to pomalidomide-engaged CRBN in vitro, but not destabilized by the same compound in cells, our results suggest that small changes in ZF-binding affinity disproportionally influence ZF degradation in cells.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > In silico identification of novel ZFs that interact with the drug-CRBN interface
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“explaining preferential binding of IKZF1/IKZF3 to CRBN engaged with pomalidomide or lenalidomide over thalidomide in vitro (6), and the contribution of this residue to compound selectivity in vivo (fig. S5E).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
What the sources say
- Not checked — no full text of the sourcecites [6] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results show that IKZF1 ZF2 is the primary determinant for drug binding, and identify features of ZF3 that contribute to high affinity binding to the drug-CRBN complex (Fig. 1A and fig. S4B).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Substitution of a ZF residue at one site of the CRBN interface can be compensated by amino acid changes at another site of the ZF, explaining the observed epistatic properties of the ZF degrons.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“While the effects are small, our findings suggest that different thalidomide analogs target different ZFs for degradation, including ZFs identified by computational docking, rendering them suitable candidates for drug development.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Different thalidomide analogs target distinct sets of ZFs for degradation
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As the CRBN groove is narrow (Fig. 4C), ZF-CRBN interactions at both sides of the groove together determine binding.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Structures of CRBN bound to pomalidomide and two different ZF degrons
plaindirect- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For each experiment, three technical replicates and three experimental replicates were performed unless otherwise indicated.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Protein degradation reporter analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The ~800 C2H2 ZF-containing proteins are the largest class of putative transcription factors in the human proteome (13).”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
What the sources say
- Not checked — no full text of the sourcecites [13] source
hedged- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To execute the screen we performed three technical replicates of the following”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Saturation Mutagenesis
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Three technical replicates were carried out per experiment.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Time-resolved fluorescence resonance energy transfer (TR-FRET)
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To reduce noise and false positives caused by zinc fingers with low numbers of reads, zinc fingers with less than 200 raw reads in the DMSO-treated unsorted control were removed from the library.”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > C2H2 zinc finger library screen
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To reduce noise, three filtering criteria were applied independently to remove the least reliable zinc fingers”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > C2H2 zinc finger library screen
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To execute the screen, we performed three experimental replicates of the following”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > C2H2 zinc finger library screen
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The recent discovery that the small immunomodulatory drug thalidomide induces ubiquitylation and degradation of SALL4 by the CRL4CRBN E3 ubiquitin ligase [50] has demonstrated that this transcription factor can be targeted for cancer therapy [48, 50].”
From SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma (2024) · cites this paper as [50]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The recent discovery that the small immunomodulatory drug thalidomide induces ubiquitylation and degradation of SALL4 by the CRL4CRBN E3 ubiquitin ligase [50] has demonstrated that this transcription factor can be targeted for cancer therapy [48, 50].”
From SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma (2024) · cites this paper as [50]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“MGs can recruit or degrade more than one target; for example, pomalidomide (POM) and CC-220 recruit and degrade transcription factor IKZF1 along with SALL4 and several other targets3,5,6.”
From Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon (2023) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Studies have shown that protein degradation is chemotype dependent and that single atom changes among lenalidomide and pomalidomide result in the degradation of different protein populations3,6, yet the origin of the observed selectivity for a given target (or targets) is unclear.”
From Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon (2023) · cites this paper as [3]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“This behaviour is reminiscent of CRL4CRBN and thalidomide analogues11,26, where an apparent affinity threshold must be overcome to drive drug-induced target degradation.”
From The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K (2020) · cites this paper as [26]
The cited source says what the claim attributes to it.
In the citing paper
“Strikingly, G3BP2 lacks key contacts with the CRBN CULT domain commonly involved in neosubstrate recruitment25–28, which distinguishes the binding mode of G3BP2 from other structurally characterized CRBN targets (Fig. 5a–d and Extended Data Fig. 10).”
From Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry (2026) · cites this paper as [28]
The cited source says what the claim attributes to it.
In the citing paper
“Biochemical studies with IKZF1 in the presence of pomalidomide indicate that ZF2-3 binds more potently than ZF2 alone3, suggesting that for these”
From Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon (2023) · cites this paper as [3]
The cited source says what the claim attributes to it.
In the citing paper
“Additionally, it is the third binding mode for ZFs to CRBN:MG complexes adding to our understanding of the binding of single zinc fingers such as IKZF13,7 and ZNF6923, and the binding of two zinc fingers including C-terminal ancillary ZF3 in the IKZF2 ZF2-3 complex9,10.”
From Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon (2023) · cites this paper as [3]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Thal efficiently directs SALL4 to Cullin4/Cereblon (CRL4CRBN)-mediated degradation [49, 50] exclusively in humans, primates, and rabbits [48].”
From SALL4 is a CRL3REN/KCTD11 substrate that drives Sonic Hedgehog-dependent medulloblastoma (2024) · cites this paper as [50]
Experimental — accuracy not yet measuredIn the citing paper
“Without a ligand-binding pocket, classic neo-substrates of IMiDs-bound CRBN, such as IKZF1 and CK1α, are not expected to have an affinity towards the compounds12,15.”
From Defining molecular glues with a dual-nanobody cannabidiol sensor (2022) · cites this paper as [12]
In the citing paper
“These compounds, collectively known as immunomodulatory drugs (IMiDs), can promote the degradation of a host of cellular proteins by extending the subpar interfaces they form with CRBN, the substrate receptor of the CUL4-RBX1-DDB1 (CRL4) ubiquitin ligase complex9–20.”
From Defining molecular glues with a dual-nanobody cannabidiol sensor (2022) · cites this paper as [12]
In the citing paper
“In brief, IMiDs bind the E3 ligase cereblon (CRBN), thus complementing a surface patch that subsequently recruits a variety of C2H2 zinc finger transcription factors for ubiquitination and degradation.48−51”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [51]
In the citing paper
“Indeed, the holo form of CRBN was used in a large-scale docking run to predict C2H2 zinc-finger degrons.51”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [51]
In the citing paper
“which has been reported to induce degradation of multiple members of the C2H2 zinc finger protein family through a ‘molecular glue’ type mechanism (Sievers et al., 2018)”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Sievers et al., 2018
In the citing paper
“Moreover, analogs of rapamycin and thalidomide can still maintain binding to FKBP12 and cereblon respectively, but shift their neo-substrate binding profiles to confer new and distinct biological functions 13,14.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [14]
In the citing paper
“Iberdomide has also shown efficacy in models of systemic lupus erythematosus in vitro where treatment can decrease production of auto-antibodies, and trials are ongoing in this disease setting119.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [119]
In the citing paper
“Our assay for CRL4CRBN ubiquitylation of IKZF was established based on findings that ZF2 mediates tight immunomodulatory-drug dependent interaction sufficient to target degradation, UBE2D3 contributes to stability of CRL4CRBN neomorphic substrates in cells57,60,61.”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [60]
In the citing paper
“Our assay for CRL4CRBN ubiquitylation of IKZF was established based on findings that ZF2 mediates tight immunomodulatory-drug dependent interaction sufficient to target degradation, UBE2D3 contributes to stability of CRL4CRBN neomorphic substrates in cells57,60,61.”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [60]
In the citing paper
“A well-characterized example of off-target activities of PROTACs are CRBN-based PROTACs because CRBN ligands, including thalidomide, pomalidomide, and lenalidomide, used for the CRBN-targeted PROTACs can recruit several neo-substrates such as SALL4, IKZF1, and IKZF3 to CRBN to induce their degradation [207, 208]. This can lead to some adverse effects including teratogenic effect and cardiovascular”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [208]
In the citing paper
“A proteomic approach has also shown that a large subset of zinc finger proteins, in particular those containing Cys2-His2 (C2H2) zinc finger domains that exhibit the specific glycine containing turn structure, can be degraded by IMiD-bound CRBN.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [78]
In the citing paper
“However, target-specific docking sites can be presented by the thalidomide derivative, as is the case with CC-885 and GSPT1 [77], as well as pomalidomide and the zinc finger proteins IKZF1 or ZNF692 [78].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [78]
In the citing paper
“Structural analysis revealed the minimal requirement for IMiD targets to participate in the CRBN–IMiD interaction to be a surface-exposed turn, containing a precisely positioned glycine residue [77, 78].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [78]
In the citing paper
“Additionally, different IMiDs have been shown to induce the degradation of distinct Zn-finger proteins, which is attributed to steric and structural properties of the targets, and the CRBN–IMiD surface [78].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [78]
In the citing paper
“IMiDs degrade diverse arrays of ZnF transcription factors 9 ,”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [9]
In the citing paper
“Structural studies on VHL and CRBN show that these CullinRING E3 ligases (CRLs) form large, modular, U-shaped complexes in which adaptor proteins mediate the interaction between the substrate-binding element (VHL or CRBN) and Cullin scaffolds that bind the RING-domain protein RBX1, leading to the recruitment of a ubiquitinconjugated E2 (refs 9,46,47,48,49,50,51,52 )”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [9]
In the citing paper
“This unique structural arrangement is preserved in unrelated IMiD targets such as the zinc-finger proteins IKFZ1 and ZNF692 (ref. 9 ), the kinase CK1α 47 and the GTP-binding protein GSPT1 (ref. 48 ),”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [9]
In the citing paper
“Rather, the target engages in direct interaction with the CRBN-bound phthalimide group via a β-hairpin that is structurally conserved in all available complex structures, where a critically positioned glycine abuts against the phthalimide in a binding pose that would be incompatible with any other amino acid (Fig. 2d).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [9]
In the citing paper
“and was used to identify novel zinc-finger proteins degraded by thalidomide analogues 9 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [9]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > Discussion
“28 of the ~50–150 additional C2H2 ZFs nominated by in silico docking were shown to bind the drug-CRBN complex”
§ Defining the human C2H2 zinc-finger degrome targeted by thalidomide analogs through CRBN > In silico identification of novel ZFs that interact with the drug-CRBN interface
“Based on biological relevance, 21 of these ZFs were selected and tested for CRBN engagement in TR-FRET experiments”
Citations
Cites
Features and development of Coot
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Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
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“Thalidomide, lenalidomide, and pomalidomide mediate CRL4dependent degradation of a larger number of proteins than previously appreciated through a C2H2 ZF degron (3, 4, 16).”
BackgroundMethodInfluentialSelf-citationNew and continuing developments at PROSITE
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“3A) highlighted shared residues that are part of the PROSITE C2H2 ZF search motif (IKZF3 C148, C151, H164, H168, and F155), residues that stabilize the ternary fold of the ZF domain (IKZF3 L161), and residues that frequently appear within C2H2 ZF domains (IKZF3 G152).”
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Tiny Titans: Nanobodies as Powerful Tools for TR‐FRET Assay Development
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“Ikaros (IKZF1) and Aiolos (IKZF3) have been established for targeted destruction by imides (thalidomide, lenalidomide, pomalidomide) to exert their anti-cancer activities in multiple myeloma [13].”
BackgroundAn Automated Electrochemical Flow Platform to Accelerate Library Synthesis and Reaction Optimization
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Druggable Transcriptional Networks in the Human Neurogenic Epigenome
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“Note that while this work was being prepared for submission, Thomä and colleagues reported the interaction of a large collection of zinc fingers proteins with CRBN, including those reported here (44).”
BackgroundDegraders on Demand: Engineering Smart Nanocarriers for PROTAC Delivery
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G protein-coupled receptor–targeted proteolysis-targeting chimeras in cancer therapeutics
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Thalidomide-induced limb malformations: an update and reevaluation
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Opportunities in proximity modulation: Bridging academia and industry
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“42 In parallel, some aryl sulfonamides, such as indisulam, were found to hijack CRL4 DCAF15 and degrade the splicing factor RBM39.”
Self-citationPersonalized precision medicine
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IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling
Dunbar, K. J., Macartney, T., & Sapkota, G. P. (2020) · Life Science Alliance · doi:10.26508/lsa.202000804 · Cited by 9
“IMiDs bind neo-substrates at slightly different angles, thus presenting different residues to the ROC1 E3 ligase which may explain the differences in protein degradation noted between various IMiD compounds (31).”
Koochaki, S., Slabicki, M. M., Lumpkin, R. J., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102484 · Cited by 9
“It has also been hypothesized that CBL may negatively regulate CSF2RB-mediated signaling, but recent evidence suggests that CBL specifically ubiquitinates JAK2 and not CSF2RB directly (12).”
BackgroundSelf-citationMachine learning proteochemometric models for Cereblon glue activity predictions
Prael, F. J., Cox, J. W., Sturm, N., Kutchukian, P. S., Forrester, W. C., Michaud, G. A., Blank, J., Shen, L., & Rodríguez-Pérez, R. (2024) · Artificial Intelligence in the Life Sciences · doi:10.1016/j.ailsci.2024.100100 · Cited by 10
Exploration of the Tunability of BRD4 Degradation by DCAF16 Trans -labelling Covalent GluesPreprint
Hassan, M. M., Li, Y.-D., Ma, M. W., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.07.561308 · Cited by 9
Self-citationMerino‐Cacho, L., Barroso‐Gomila, O., Pozo-Rodríguez, M., Muratore, V., Guinea-Pérez, C., Serrano‐Morrás, Á., Pérez, C., Cano-López, S., Urcullu, A., Azkargorta, M., et al. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02091-5 · Cited by 8
“Notably, among the new putative neosubstrates presented here, some of them have features typical for thalidomide recognition, as the zinc finger or the G-loop, as is the case for KAISO (ZBTB33) or CSDE1, respectively [39, 53].”
Controlling CRISPR-Cas9 genome editing in human cells using a molecular glue degrader
Khajanchi, N., Patel, V., Dua, R., Kabra, M., Pattnaik, B. R., & Saha, K. (2025) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2025.102640 · Cited by 8
Research progress on covalent inhibitors targeting alkaline amino acids
Zhao, B., Xu, S., Zhou, S., Jiang, X., Jiang, A., Lei, H., & Zhai, X. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108800 · Cited by 8
ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC
Tran, N. L., Jiang, J., Ma, M., Gadbois, G. E., Gulay, K. C. M., Verano, A. L., Schiavon, C. R., Rebollo, E., Zhou, H., Huang, C., et al. (2025) · Nature Chemical Biology · doi:10.1038/s41589-025-01978-1 · Cited by 14
“3n) 38 .”
Synthesis and Structure–Activity Relationships of CRBN-Recruiting ZBTB11 Molecular Glue Degraders
Jiang, J., Tran, N. L., Svendsen, E., Wang, E. S., & Ferguson, F. M. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c01352 · Cited by 6
Drugging the undruggable: Chemical and biological insights into molecular glues in the pipeline
Metwally, K. A., Yahya, G., & Abo-Dya, N. E. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.118132 · Cited by 9
Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer
Lu, X., Wang, X., Yang, Z., Wang, X., Wang, L., Xu, C., Lo, I., Geng, C., Wang, L., Pu, Y., et al. (2026) · Nature · doi:10.1038/s41586-026-10613-5 · Cited by 15
“Inspired by the conserved β-hairpin G-loop topology in CRBN neo-substrates 32,34,40 , we mapped two analogous structural motifs in HuR (G58/G144 loops) by molecular docking.”
Tracy, W. F., Davies, G. H. M., Jia, L., Evans, E. D., Sun, Z., Buenviaje, J., Khambatta, G., Yu, S., Shi, L., Shanmugasundaram, V., et al. (2024) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.4c00297 · Cited by 9
Murawska, G. M., Vogel, C., Jan, M., Lu, X., Schild, M., Slabicki, M. M., Zou, C., Zhanybekova, S., Manojkumar, M., Petzold, G., et al. (2022) · ACS Chemical Biology · doi:10.1021/acschembio.1c00771 · Cited by 9
Self-citationFunctional assays for transcription mechanisms in high-throughput
Qiu, C., & Kaplan, C. D. (2019) · Methods · doi:10.1016/j.ymeth.2019.02.017 · Cited by 9
Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry
Annunziato, S., Quan, C., Donckele, E. J., Lamberto, I., Bunker, R. D., Zlotosch, M., Schwander, L., Murthy, A., Wiedmer, L., Staehly, C., et al. (2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01738-8 · Cited by 9
“Most MGD-dependent CRBN neosubstrates share a common structural recognition motif composed of a β-hairpin α-turn carrying a key glycine residue commonly referred to as the G-loop 26–28 .”
Self-citationHatakeyama, K., Kikushige, Y., Ishihara, D., Yamamoto, S., Kawano, G., Tochigi, T., Miyamoto, T., Sakoda, T., Christoforou, A., Kunisaki, Y., et al. (2024) · Blood Advances · doi:10.1182/bloodadvances.2023010080 · Cited by 10
“28,29 This suggests the possibility that THBS-1 could interact with cereblon via the zinc-fi nger structure commonly observed in cereblon substrates.”
BackgroundChen, S., Solazzo, R., Fouché, M., ROTH, H. ‐., Dittrich, B., & Riniker, S. (2025) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.5c00736 · Cited by 8
Zhang, X., Dhruv, H., Deng, Q., Tudor, M., Bechtel, N., Nagilla, R., Jolivette, L. J., Rice, C., Orth, P., Behshad, E., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00668 · Cited by 9
Jin, Y., Liao, X., Zhang, J., Duan, H., Xu, R., Luo, X., Yu, X., Li, B., Wang, J., Li, X., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c01159 · Cited by 9
Mechanisms that matter: unbiased cellular screening for degraders
Burston, H. E., Rosethorne, E. M., Cavallo, F., Jordan, A. M., Baruah, P. S., Swift, D., & Hjerpe, R. (2025) · npj Drug Discovery. · doi:10.1038/s44386-025-00028-z · Cited by 7
Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells
Brennan, P. J., Saunders, R. E., Spanou, M., Singleton, S. E., Serafini, M. T., Sun, L., Heger, G., Konopacka, A., Beveridge, R. D. D., Taylor, C. C., et al. (2025) · ACS Chemical Biology · doi:10.1021/acschembio.5c00751 · Cited by 10
Machine learning, docking, or physics for structure prediction of ligand-induced ternary complexes
Solazzo, R., Chen, S., & Riniker, S. (2026) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2025.103217 · Cited by 7
Differential Analysis of Cereblon Neosubstrates in Rabbit Embryos Using Targeted Proteomics
Federspiel, J. D., Catlin, N. R., Nowland, W. S., Stethem, C. M., Mathialagan, N., Ocaña, M. F., & Bowman, C. (2024) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2024.100797 · Cited by 8
“Available literature has shown a decrease in response to CC-220 (40, 41) but no changes with the IMiDs used here.”
Lovato, K., Loskot, D., Gelin, C. F., Zhu, L., Chaudhry, C., Vellore, N. A., Rosario, A. M. D., Courtney, T. M., Miller, S. P., Cho, J., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c03157 · Cited by 7
Targeted protein degradation: from small molecules to complex organelles—a Keystone Symposia report
Cable, J., Weber-Ban, E. U., Clausen, T., Walters, K. J., Sharon, M., Finley, D. J., Gu, Y., Hanna, J. W., Feng, Y., Martens, S., et al. (2022) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14745 · Cited by 6
Self-citationDesign and Applications of Bifunctional Small Molecules in Biology
Boyd, S. R., Chang, L., de Rezende, W. C., Raji, I. O., Kandel, P., Holmes, S. L., & Young, D. W. (2020) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2020.140534 · Cited by 7
From Degraders to Molecular Glues: New Ways of Breaking Down Disease‐Associated Proteins
Nagel, Y. A., Britschgi, A., & Ricci, A. (2021) · Wiley eBooks · doi:10.1002/9783527826872.ch2 · Cited by 6
Molecular Glue Degraders: From Serendipity to Hunting and Design
Nieto‐Barrado, L., Domostegui, A., & Mayor‐Ruiz, C. (2022) · Wiley eBooks · doi:10.1002/9783527836208.ch6 · Cited by 7
Klemm, N., Schimmer, R. R., Konrad, N. K., Thelen, F., Fullin, J., Topçu, E., Koch, C., Treacy, M., Leventhal, M. J., Bühler, M. M., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-1136 · Cited by 9
“To this end, we utilized a previously described degron-tagging system (12, 21) to generate a LV expression construct carrying the full-length cDNA of R248Q fused to a degron tag and a GFP tag on its N-and C-terminus, respectively.”
Self-citationXu, Y., Hu, H., Ran, Y., Zhao, W., Guo, A., Nie, H., Zhai, L., Yin, G., Cheng, J., Tao, S., et al. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202507254 · Cited by 7
PROTACs: Walking through hematological malignancies
Malhab, L. J. B., AlSafar, H. S., Ibrahim, S. M., & Rahmani, M. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1086946 · Cited by 6
“It is important to note that major advances in this field have been catalyzed by the discoveries from the work of Benjamin Ebert’s group that the direct molecular target of thalidomide and other derived immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide is CRBN E3 ligase (Kronke et al., 2014a; Kronke…”
BackgroundIKZF2 Degradation: It′s Time to Take into Account it When Designing Cereblon‐Based PROTACs
Li, M. (2024) · ChemBioChem · doi:10.1002/cbic.202400365 · Cited by 7
Lessons from natural molecular glue degraders
Cao, S. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230836 · Cited by 5
Methods to characterize and discover molecular degraders in cells
Lin, Z., & Woo, C. M. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00261b · Cited by 7
Feng, D., Li, W., Wu, W. D., et al. (2023) · Journal of Oncology · doi:10.1155/2023/2736932 · Cited by 6
“As for IKZF3 (Aiolos), it belongs to the family of Cys2-His2 zinc fnger proteins, which is a lymphocyte lineage transcription factor necessary for the survival of the malignant [35].”
BackgroundShining light on reprogramming Tregs for cancer therapy
Wang, E. S., & Gray, N. S. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.02.009 · Cited by 6
Targeted Protein Degradation: Principles, Strategies, and Applications
He, T., Wen, C., Yang, G., & Yang, X. (2023) · Advanced Biology · doi:10.1002/adbi.202300083 · Cited by 6
Probing biological mechanisms with chemical tools
Kang, C., & Keller, T. H. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104656 · Cited by 6
The roles of zinc finger proteins in non-alcoholic fatty liver disease
Li, G., Ma, X., & Xu, L. (2020) · Liver Research · doi:10.1016/j.livres.2020.01.001 · Cited by 7
Review and Prospect of Tissue-agnostic Targeted Strategies in Anticancer Therapies
Peng, Y., Tao, H., Gao, Y., Yang, Y., & Chen, Z. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200616143247 · Cited by 6
Fantastic Molecular Glues and Where to Find them
Gillingham, D. G. (2021) · CHIMIA International Journal for Chemistry · doi:10.2533/chimia.2021.439 · Cited by 6
Márquez-Cantudo, L., Ramos, A., Coderch, C., & de Pascual‐Teresa, B. (2021) · Molecules · doi:10.3390/molecules26185606 · Cited by 8
“It has also been found that the IMiD-bound CRL4CRBN system is able to ubiquitinate other C2H2 Zn-finger proteins [71], glutamine synthetase enzyme [72], and the serine/threonine protein kinase CK1 [73].”
BackgroundFinding High-Quality Metal Ion-Centric Regions Across the Worldwide Protein Data Bank
Yao, S., & Moseley, H. (2019) · Molecules · doi:10.3390/molecules24173179 · Cited by 6
“Protein metal binding is part of many biochemical mechanisms including signal transduction, enzyme catalysis, and protein structural integrity [3-5].”
BackgroundExpanding the reach of molecular glue degraders
Hartmann, M. D. (2025) · Science · doi:10.1126/science.ady4446 · Cited by 6
BCL6 confers resistance to HDAC inhibitors in DLBCL
Gao, F., Zhang, Y., Li, Q., Rong, R., He, L., He, L., Li, B., & Zhuang, W. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116466 · Cited by 5
Xu, Q., Liu, W., Liu, H., & Zheng, Z. (2025) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5c00387 · Cited by 9
Rewiring the Fusion Oncoprotein EWSR1::FLI1 in Ewing Sarcoma with Bivalent Small Molecules
Bond, M. J., Golden, R. P., DiGiovanni, G., Howard, B., Sarott, R. C., Karim, B. A., Gourisankar, S. P., Alexe, G., Ross, K. N., Jones, H. M., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c05634 · Cited by 6
Chen, L., Aleman, A., Larráyoz, M., Chiu, H., Zhao, J., Oekelen, O. V., Kelly, G., Kim‐Schulze, S., Laganà, A., Jagannath, S., et al. (2026) · Blood · doi:10.1182/blood.2025030891 · Cited by 7
Self-citationMolecular and Structural Characterization of Lenalidomide-Mediated Sequestration of eIF3i
Lin, Z., Shen, D., Yang, B., & Woo, C. M. (2022) · ACS Chemical Biology · doi:10.1021/acschembio.2c00706 · Cited by 5
Proteorhodopsin insights into the molecular mechanism of vectorial proton transport
Bukhdruker, S. S., Gushchin, I., Shevchenko, V., Kovalev, K., Polovinkin, V., Tsybrov, F. M., Astashkin, R., Alekseev, A. A., Mikhaylov, A., Bukhalovich, S. M., et al. (2025) · Science Advances · doi:10.1126/sciadv.adu5303 · Cited by 10
“( 101 – 104 )].”
Profiling CELMoD-Mediated Degradation of Cereblon Neosubstrates
Thompson, J. W., Clayton, T., Khambatta, G., Bateman, L. A., Carroll, C. W., Chamberlain, P. P., & Matyskiela, M. E. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1665-9_15 · Cited by 5
Exploring the impact of dexamethasone on gene regulation in myeloma cells
Gaborit, V., Cruard, J., Guérin‐Charbonnel, C., Derrien, J., Alberge, J.-B., Douillard, E., Devic, M., Deshayes, S., Campion, L., Westermann, F., et al. (2023) · Life Science Alliance · doi:10.26508/lsa.202302195 · Cited by 8
“A recent study showed that these TFs are degraded by IMIds (Sievers et al, 2018).”
BackgroundE3 ubiquitin ligases in lung cancer: Emerging insights and therapeutic opportunities
Basu, B., Kal, S., Karmakar, S., Basu, M., & Ghosh, M. K. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122333 · Cited by 5
Selective and Potent Molecular Glue Degraders for NIMA‐Related Kinase 7
Chen, L., Huang, L., Wen, W., Zeng, P., Wu, Y., Han, Q., Chen, X., Guo, Z., Yu, H., Lu, W., et al. (2025) · Angewandte Chemie · doi:10.1002/ange.202500169 · Cited by 5
Targeting transcription factors
Crunkhorn, S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.231 · Cited by 5
Molecular glue CELMoD compounds are allosteric regulators of cereblon conformationPreprint
Watson, E. R., Novick, S. J., Matyskiela, M. E., Chamberlain, P. P., de la Peña, A. H., Zhu, J., Tran, E., Griffin, P. R., Wertz, I. E., & Lander, G. C. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.02.498551 · Cited by 5
Targeting transcription factors through an IMiD independent zinc finger domain
Liu, B. H., Liu, M., Radhakrishnan, S., Dai, M.-Y., Jaladanki, C. K., Gao, C., Tang, J. P., Kumari, K., Go, M. L., Vu, K. A. L., et al. (2025) · EMBO Molecular Medicine · doi:10.1038/s44321-025-00241-3 · Cited by 8
“Besides the known targeted proteins of IMiDs such as Ikaros (IKZF1), Aiolos (IKZF3), Casein kinase 1 alpha (CK1 α ), GSPT1, and SALL4, a set of Cys2-His2 (C2H2) zinc fi ngers have also been identi fi ed to be degraded by thalidomide analogs (Sievers et al, 2018).”
PROTACs in targeted protein degradation: Advances in development and AI-enhanced drug discovery
Du, M., Liu, T., Wang, W., Fan, S., Tian, M., Du, Q., Wang, Z., Li, X., Liu, X., Xia, Q., et al. (2026) · European Journal of Medicinal Chemistry Reports · doi:10.1016/j.ejmcr.2026.100332 · Cited by 4
Probing the E3 Ligase Adapter Cereblon with Chemical Biology
Xu, W., & Woo, C. M. (2025) · Accounts of Chemical Research · doi:10.1021/acs.accounts.5c00059 · Cited by 4
Pugnetti, L., Curci, D., Bidoli, C., Gerdol, M., Celsi, F., Renzo, S., Paci, M., Lega, S., Nonnis, M., Maestro, A., et al. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114927 · Cited by 4
Cereblon-Targeting Ligase Degraders in Myeloma
Lee, H., Neri, P. E., & Bahlis, N. J. (2024) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2024.01.001 · Cited by 5
Myogenesis gone awry: the role of developmental pathways in rhabdomyosarcoma
Gustafson, A. L., Durbin, A. D., Artinger, K., & Ford, H. L. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1521523 · Cited by 7
Illuminating ubiquitination mechanisms: How cryo-EM has shed light on Cullin RING E3 ligase function
Rizvi, Z., & Lander, G. C. (2025) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2025.103055 · Cited by 5
The Contribution of Native Protein Complexes to Targeted Protein Degradation
Glennie, L., Curnutt, N., Sathe, G. J., Chatelier, B. L., Goff, F., Zhao, J.-F., Cartwright, T. N., Dunbar, K. J., Wood, N. T., Macartney, T., et al. (2026) · ACS Chemical Biology · doi:10.1021/acschembio.6c00098 · Cited by 4
Nutt, M. J., Yee, Y. S., Buyan, A., Andrewartha, N., Corry, B., Yeoh, G. C., & Stewart, S. G. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113353 · Cited by 4
Effects of cereblon on stress-activated redox proteins and core behavior
Akber, U., Bong, S., Park, Z., & Park, C. (2022) · Brain Research · doi:10.1016/j.brainres.2022.148054 · Cited by 3
Clinical Trials of Repurposing Medicines in Acute Myeloid Leukemia
Andresen, V., & Gjertsen, B. T. (2019) · The Cancer Journal · doi:10.1097/ppo.0000000000000363 · Cited by 4
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“Synthetic Methods General Procedures Unless otherwise stated, all reactions were performed in oven-dried or flame-dried Fisherbrand® borosilicate glass tubes (Fisher Scientific, 1495925A, 13 ́ 100 mm) with a black phenolic screw cap (13-425) under an atmosphere of dry nitrogen.”
Wan, H., Aravamuthan, V., Williams, S., Wartchow, C. A., Duca, J. S., & Pearlstein, R. A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.29.466510 · Cited by 4
Sylvain, A., Stoehr, N., Ma, F., Cernijenko, A., Schröder, M., Khoshouei, M., Vogelsanger, M., Schoenboerner, M., Burke, A. A., Pasupuleti, R., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.06.622079 · Cited by 4
Comparative assessment of co-folding methods for molecular glue ternary structure predictionPreprint
Liao, Y., Zhu, J., Xie, J., Lai, L., & Pei, J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.25.655997 · Cited by 4
“It is predictable as WIZ belongs to the Cys2-His2 (C2H2) subfamily, some of which are well-investigated zinc finger substrates targeted by CRBN-MGD complexes 46 .”
Lin, H., Yu, X. F., Zheng, H., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.08.658535 · Cited by 4
“The discovery of novel molecular glues, however, remains a significant challenge due to the indirect nature of their mechanism, which complicates rational design efforts 8,13 .”
Xu, Y., Hu, H., Ran, Y., Zhao, W., Guo, A., Nie, H., Zhai, L., Yin, G., Cheng, J., Tao, S., et al. (2025) · Angewandte Chemie · doi:10.1002/ange.202507254 · Cited by 3
Luchini, G., Liu, S., Powers, H. L., Cherney, E. C., Zhu, J., Danga, K., Thompson, J. W., Shi, L., Pagarigan, B., Wei, D. D., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c01919 · Cited by 3
A Glutathione S-Transferase Pi Molecular Glue Tethers Splicing Factors and Remodels Cell Metabolism
Leace, D. M., Ware, M. L., Murtagh, O. L., Tsai, H.-K., Chang, C., & Hsu, K. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c06951 · Cited by 3
Advances in light-activated PROTACs and phototherapy-combined approaches for cancer treatment
Zhang, W., Li, S., Yuan, H., & Zhao, J. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.118310 · Cited by 3
Molecular glue degraders: Rational design, specificity engineering, and advanced delivery
Ma, L., Wang, N., Zhu, J., Wu, L., He, S., & Zhang, B. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.02.020 · Cited by 5
“However, in practice, subtle conformational differences or insufficient ternary complex cooperativity can abrogate degradation even when binary binding is detectable 8,91 .”
Safety considerations for cereblon-recruiting targeted protein degraders
Garside, H., Aslamkhan, A. G., Daniels, D. L., Datta, K., Pedersen, M. E., Hukkanen, R. R., Jones, L. H., Ketter, N., Lahoti, T. S., Loberg, L. I., et al. (2026) · Nature Reviews Drug Discovery · doi:10.1038/s41573-026-01426-2 · Cited by 6
“Broad proteomics screening using mass spectrometry-based and functional genomics-based approaches have been used to identify IMiD-mediated CRBN neosubstrates 6,57 .”
Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders
Crowe, C., & Ciulli, A. (2026) · Chemical Reviews · doi:10.1021/acs.chemrev.5c00800 · Cited by 6
Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues
Ojeda, S., Wang, M., Baek, K., Bourgeois, W., Sommerschield, A., Yue, H., Metivier, R. J., Karagiannis, P., Levitz, T. S., Xiong, Y., et al. (2026) · Science · doi:10.1126/science.aef5391 · Cited by 5
Zhang, R., Zheng, Y., Xiang, F., & Zhou, J. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116756 · Cited by 5
Meng, S., Meng, Y., Yang, X., Yu, W., Li, B., Liu, T., Zhang, J., Ren, X., & Zhang, L. (2025) · BMC Biology · doi:10.1186/s12915-025-02153-7 · Cited by 3
Guo, Y. L., Song, Y., Wang, H., Yang, L., Zhang, J., Shen, Z., Kan, W., Wang, Y., Duan, H., Geng, S., et al. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.09.009 · Cited by 4
“Using previously reported methods 47,48 , we established a degradation imaging screening platform targeting ZF degrons and tested the CELMoD library (Fig.”
Preclinical Studies of PROTACs in Hematological Malignancies
Fuchs, O., & Bokorová, R. (2021) · Cardiovascular & Haematological Disorders - Drug Targets · doi:10.2174/1871529x21666210308111546 · Cited by 3
Targeting the Transcriptome Through Globally Acting Components
Parrello, D., Vlasenok, M., Kranz, L. A., & Nechaev, S. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.749850 · Cited by 3
“Targeting specific factors such as transcription factors causative of certain cancers is becoming feasible (Sievers et al., 2018; Duffy and Crown, 2021), but is limited by an uncertainty in how these and other factors may function in different cellular contexts.”
BackgroundLiu, D., Qiu, J., Hu, S., et al. (2022) · Journal of Chemical & Engineering Data · doi:10.1021/acs.jced.2c00162 · Cited by 3
Kowalski, T. W., Feira, M. F., Lord, V. O., Gomes, J. D. A., Giudicelli, G. C., Fraga, L. R., Sanseverino, M. T. V., Recamonde‐Mendoza, M., Schüler‐Faccini, L., & Vianna, F. S. L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411515 · Cited by 3
“However, few TFs have been identified when studying the C2H2 degrome induced by IMiDs [23].”
BackgroundBarbosa, B. M. G., Sfyaki, A., Rafael, S., José‐Duran, F., Pous, J., Sánchez, C., Perez‐Lopez, C., Vilanova, M., Cigler, M., Gay, M., et al. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202316730 · Cited by 3
Development of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators
Liu, Y., Nowak, R. P., Che, J., Donovan, K. A., Huerta, F., Liu, H., Metivier, R. J., Fischer, E. S., & Jones, L. H. (2024) · RSC Medicinal Chemistry · doi:10.1039/d3md00652b · Cited by 3
Metadata
- Authors
- Sievers, Q. L., Petzold, G., Bunker, R. D., Renneville, A., Słabicki, M., Liddicoat, B. J., Abdulrahman, W., Mikkelsen, T., Ebert, B. L., & Thomä, N. H.
- Affiliations
- Broad Institute (US)
- Friedrich Miescher Institute (CH)
- Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
- Corresponding author
- Sievers, Quinlan L.
- Petzold, Georg
- Ebert, Benjamin L.
- Thomä, Nicolas H.
- ORCID
- Venue
- Science
- Published
- 2018-11-02
- Volume
- 362
- Issue
- 6414
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6326779
- OpenAlex
- W2899147964
- Semantic Scholar
- bb030c91bbd9cc5d2deb2194277c21440f3a6f5f
- Cited by
- 537
- References
- 42
- Citations by year
- 2026: 78 · 2025: 87 · 2024: 73 · 2023: 80 · 2022: 58 · 2021: 65 · 2020: 59 · 2019: 34 · 2018: 2
- FWCI
- 14.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (R01HL082945, P01CA108631)
- National Institute of General Medical Sciences (T32GM007753)
- European Molecular Biology Organization (aALTF 761-2016)
- Human Frontier Science Program (LT000210/2014)
- H2020 Marie SkÅodowska-Curie Actions (702642)
- European Research Council (666068)
- National Health and Medical Research Council (APP1124979)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- C2H2 zinc finger, cereblon, thalidomide analogues, E3 ubiquitin ligase, protein degradation, transcription factor targeting, undruggable proteins, proteome-wide screening
- MeSH terms
- CYS2-HIS2 Zinc Fingers, Lenalidomide, Amino Acid Sequence, Humans, Peptide Hydrolases, Thalidomide, Proteome, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Ikaros Transcription Factor, Receptors, Interleukin-17, Ubiquitination, HEK293 Cells, Proteolysis
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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