Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
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Drug With a (Re)Purpose: Thalidomide, once infamous for its deleterious effects on fetal development, has re-emerged as a drug of great interest because of its beneficial immunomodulatory effects. A derivative drug called lenalidomide significantly extends the survival of patients with multiple myeloma, but the molecular mechanisms underlying its efficacy remain unclear (see the Perspective by Stewart ). Building on a previous observation that thalidomide binds to cereblon, a ubiquitin ligase, Lu et al. (p. 305 , published online 28 November) and Krönke et al. (p. 301 , published online 28 November) show that in the presence of lenalidomide, cereblon selectively targets two B cell transcription factors (Ikaros family members, IKZF1 and IKZF3) for degradation. In myeloma cell lines and patient cells, down-regulation of IKZF1 and IKZF3 was necessary and sufficient for the drug's anticancer activity. Thus, lenalidomide may act, at least in part, by “grepurposing” a ubiquitin ligase.
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Thalidomide analogues bring zinc-finger transcription factors and other targets to CRBN, the substrate receptor of the CRL4CRBN E3 ligase.
“Thalidomide analogues recruit zinc-finger transcription factors and other targets to CRBN8–11, the substrate receptor of the cullin-RING E3 ubiquitin ligase CUL4A/B-RBX1-DDB1-CRBN (CRL4CRBN)12.”
From The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K (2020) · cites this paper as [9]
The paper reports that lenalidomide increases binding of the zinc-finger transcription factors IKZF1 and IKZF3 to CRBN, which it identifies as a CRL4 substrate receptor (Abstract; page unavailable). It does not establish recruitment of other targets: it says alternative substrates may mediate other effects. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThalidomide, lenalidomide, and pomalidomide cause ubiquitination and proteasomal degradation of IKZF1 and IKZF3 by bringing a C2H2 zinc finger domain to CRBN, the substrate receptor of CRL4CRBN.
“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.”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [3]
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)
Experimental — accuracy not yet measuredThalidomide analogs bind CRBN and change its substrate selectivity so that it recruits, ubiquitinates, and degrades proteins including IKZF1, IKZF3, CK1α, and GSPT1.
“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).”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [3]
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)
Experimental — accuracy not yet measuredProteome-wide mass spectrometry showed selective degradation of endogenous IKZF1/3 and ZFP91 in multiple cell lines.
“proteome-wide mass-spectrometry demonstrated selective degradation of endogenous IKZF1/3, and ZFP91 in multiple cell lines (3, 4, 16).”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [3]
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)
Experimental — accuracy not yet measuredThalidomide, lenalidomide, and pomalidomide mediate CRL4CRBN-dependent degradation of more proteins than previously appreciated through a C2H2 ZF degron.
“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).”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [3]
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)
Experimental — accuracy not yet measured
Recruitment of IKZF1/3 to CRL4 CRBN upon lenalidomide treatment leads to their selective ubiquitylation and proteasomal degradation, ablating their role at promoters of target genes.
“their recruitment to cRl4 cRBN , upon lenalidomide treatment, led to their selective ubiquitylation and proteasomal degradation, ablating their role at promoters of their target genes (Krönke et al. 2014;lu et al. 2014).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Krönke et al. 2014
The paper’s Abstract reports that lenalidomide promotes IKZF1 and IKZF3 binding to CRBN-CRL4, followed by selective ubiquitination and degradation. It also reports that depletion of IKZF3 de-represses the IL2 promoter in T cells. It does not establish loss of both factors’ roles at promoters of their target genes generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredBoth thalidomide and lenalidomide lack specificity for IKZF2 because it encodes a histidine in a critical thalidomide-binding position.
“Both thalidomide and lenalidomide lack specificity for iKZF2 (Krönke et al. 2014;lu et al. 2014), as it encodes a histidine in a critical thalidomidebinding position.”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Krönke et al. 2014
The passage on the IKZF3 degron (section labeled Abstract; no page given) says IKZF2 is not sensitive to lenalidomide and has a histidine at the critical position; introducing that histidine into IKZF3 caused resistance to lenalidomide-induced degradation. The copy does not establish that thalidomide likewise lacks activity against IKZF2, or identify this position as a thalidomide-binding position. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMechanistic studies later confirmed that the efficacy of lenalidomide in 5q-MDS was actually due to the recruitment of an unexpected neo-substrate: the kinase CK1α (CSNK1A1), which resides within the long arm of chromosome 5 (5q32).
“Mechanistic studies later confirmed that the efficacy of lenalidomide in 5q-MDS was actually due to the recruitment of an unexpected neo-substrate: the kinase cK1α (CSNK1A1) which resides within the long arm of chromosome 5 (5q32) (Krönke et al. 2014) (Figure 5B, i).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Krönke et al. 2014
In the paper’s concluding discussion (page unavailable), the authors suggest that lenalidomide’s efficacy in myelodysplastic syndrome may involve alternative substrates. They do not identify CK1α/CSNK1A1, establish its 5q32 location, or confirm it as the cause of efficacy in 5q-MDS; their demonstrated substrates are IKZF1 and IKZF3 in multiple myeloma. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIMiDs bind cereblon and activate its E3 ligase, leading to rapid ubiquitination and degradation of Ikaros and Aiolos.
“IMiDs bind to cereblon and activate cereblon E3 ligase activity, resulting in the rapid ubiquitination and degradation of two specific B cell transcription factors, Ikaros family zinc finger proteins Ikaros (IKZF 1) and Aiolos (IKZF3).77–79”
From Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management (2024) · cites this paper as [78]
Lenalidomide promotes the interaction between CRBN and IKZF1 and IKZF3.
“lenalidomide was shown to promote the interaction between cRBN and two members of the ikaros transcription factor family: iKZF1 and iKZF3 (gandhi et al. 2014;Krönke et al. 2014;lu et al. 2014).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Krönke et al. 2014
Lenalidomide promotes the interaction between CRL4 CRBN and both IKZF1 and IKZF3, resulting in their selective degradation.
“As such, lenalidomide can promote the interaction between cRl4 cRBN and both iKZF1 and iKZF3 resulting in their selective degradation which disrupts their role at gene promoters (Krönke et al. 2014;lu et al. 2014).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Krönke et al. 2014
IMiDs promote degradation of a host of cellular proteins by extending the subpar interfaces they form with CRBN, the substrate receptor of the CRL4 ubiquitin ligase complex.
“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 [10]
In the presence of IMiDs, CRBN E3 ligase induces proteasomal degradation of neo-substrates such as IKZF1/3, CK1α, and GSPT1.
“As described before, in the presence of IMiDs, CRBN E3 ligase induces the proteasomal degradation of a set neo-substrates, such as IKZF1/3[13,39], CK1α[40] and GSPT1[15].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [13]
PZ has no significant effect on expression of the CRBN native substrate glutamine synthetase and neosubstrates CK1α, IKZF1, and IKZF3.
“This is further supported by the observations that PZ could selectively induce Bcl-xl but not Bcl-2 poly-ubiquitination and had no significant effect on the expression of the CRBN native substrate, glutamine synthetase (GS)36, and its neosubstrates recruited by thalidomide and its analogues including CK1α37, IKZF1, and IKZF3 (ref. 38) (Supplementary Fig. 1 f, g).”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [38]
IMiDs bind the E3 ligase cereblon (CRBN), complementing a surface patch that recruits C2H2 zinc finger transcription factors for ubiquitination and degradation.
“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 [50]
IMiDs trigger CRBN-dependent proteasomal degradation of the transcription factors IKZF1 and IKZF3.
“In brief, IMiDs were first shown to trigger CRBN-dependent proteasomal degradation of the C2H2-type zing-finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3).[46][47][48]”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [47]
A glutamine residue in the second zinc-finger domain enables IMiD-induced degradation, while histidine residues in Helios (IKZF2) do not.
“The presence of a glutamine residue in their second zing-finger domain enables IMiD-induced degradation, 47 while the histidine residues in Helios (IKZF2) do not.”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [47]
Thalidomide interacts with CRBN to form a novel surface, resulting in interactions with neosubstrates IKZF1 and IKZF3 and their ubiquitination and proteasomal degradation.
“thalidomide interacts with CRBN to form a novel surface, resulting in interactions with neosubstrates such as Ikaros (IKZF1) and Aiolos (IKZF3) and their ubiquitination and subsequent proteasomal degradation.20,21”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [20]
Lenalidomide and pomalidomide induce CRBN-dependent ubiquitination and degradation of Ikaros and Aiolos, transcription factors required for development of lymphoids and survival of multiple myeloma.
“lenalidomide and pomalidomide induce CRBN-dependent ubiquitination and degradation of Ikaros and Aiolos, transcription factors required for the development of lymphoids and survival of multiple myeloma8–10.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [8]
Molecular glues constitute another important therapeutic class of targeted protein degraders.
“Molecular glues, based on the serendipitous discovery that thalidomide and its analogues act as degrader molecules, constitute another important therapeutic class1–8.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [4]
Thalidomide analogues co-opt CRBN to target IKAROS family zinc finger 1 (IKZF1) and IKZF3 for degradation, and are now considered as pioneering examples of molecular glues.
“These drugs co-opt CRBN to target IKAROS family zinc finger 1 (IKZF1) and IKZF3 for degradation3,4,24, and are now considered as pioneering examples of molecular glues.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [4]
CRBN appears to be emerging as a preferred E3 ligase for the first wave of TPD therapeutics in clinical trials.
“CRBN appears to be emerging as a preferred E3 ligase for the first wave of TPD therapeutics in clinical trials.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [4]
The approved IMiD class relies on CRBN to degrade IKZF1/IKZF3 via a molecular glue mechanism.
“Examples here include the approved IMiD class, which relies on CRBN to degrade IKZF1/IKZF3 (refs4,5) via a molecular glue mechanism”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [4]
Thalidomide and its analogues do not inhibit the enzymatic activity of CRL4CRBN, but instead confer neomorphic activity on CRBN to mediate selective ubiquitination and proteasomal degradation of IKZF1 and IKZF3 in MM cells and T cells.
“thalidomide and its analogues do not inhibit the enzymatic activity of CRL4CRBN, but instead confer neomorphic activity on CRBN to mediate the selective ubiquitination and resultant proteasomal degradation of the transcription factors Ikaros family zinc finger protein 1 (IKZF1) and IKZF3 (Aiolos) in MM cells and T cells11–13.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [11]
In 2013, thalidomide analogues were discovered to exert their therapeutic effects by acting as a molecular glue to recruit disease-relevant neosubstrate proteins to an E3 ubiquitin ligase, resulting in neosubstrate ubiquitination and proteasomal degradation.
“In 2013, thalidomide analogues were discovered to exert their therapeutic effects by acting as a molecular glue to recruit disease-relevant neosubstrate proteins to an E3 ubiquitin ligase, resulting in neosubstrate ubiquitination and, ultimately, proteasomal degradation11–13.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [11]
Proteasome inhibitors antagonize lenalidomide-induced protein degradation.
“given that proteasome inhibitors antagonize lenalidomide-induced protein degradation11,12,55.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [11]
Most known neosubstrate proteins have been identified through proteomic analyses of different cell lineages.
“Most known neosubstrate proteins have been identified through proteomic analyses of different cell lineages11,15,165,166.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [11]
When lenalidomide binds to CRBN, a new function of CRBN is induced, namely, to ubiquitinate and degrade Ikaros (IKZF1) and Aiolos (IKZF3).
“Ebert's gourp and Kaelin Jr's group independently demonstrated that when lenalidomide binds to CRBN, a new function of CRBN is induced, namely, to ubiquitinate and degrade Ikaros (IKZF1) and Aiolos (IKZF3), which are transcription factors that are known to be responsible for the maturation of B cells [25,26].”
From Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs (2016) · cites this paper as [25]
CRBN binds thalidomide in its substrate binding pocket, creating a new surface to recruit other proteins for ubiquitination and degradation, such as IKZF1, IKZF3, or CK1α.
“CRBN was shown to bind the drug thalidomide in its substrate binding pocket, thereby creating a new surface to recruit other proteins for ubiquitination and degradation, such as the transcription factors Ikaros and Aiolos (IKZF1 and 3, respectively) or the kinase CK1α [70–72].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [72]
The clinical efficacy of IMiDs is driven at least in part by their capacity to induce CRBN-mediated degradation of neo-substrates.
“The clinical efficacy of IMiDs is driven at least in part by their capacity to induce CRBN-mediated degradation of neo-substrates: cancer cells become resistant to the multiple myeloma IMiD drug lenalidomide upon mutation of a single amino acid in IKFZ3 that rescues this transcription factor from proteolytic degradation 7 ;”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [7]
Cancer cells become resistant to lenalidomide upon mutation of a single amino acid in IKZF3 that rescues this transcription factor from proteolytic degradation.
“cancer cells become resistant to the multiple myeloma IMiD drug lenalidomide upon mutation of a single amino acid in IKFZ3 that rescues this transcription factor from proteolytic degradation 7 ;”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [7]
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Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML
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- Authors
- Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., Svinkina, T., Heckl, D., Comer, E., Li, X., Ciarlo, C., Hartman, E., Munshi, N., Schenone, M., Schreiber, S. L., Carr, S. A., & Ebert, B. L.
- Affiliations
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Ebert, Benjamin L.
- ORCID
- Venue
- Science
- Published
- 2014-01-17
- Volume
- 343
- Issue
- 6168
- Pages
- 301-305
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4077049
- OpenAlex
- W2015345028
- Semantic Scholar
- bf4fc60d821257f664ef758f219b75586ad0adaa
- Cited by
- 1,879
- References
- 31
- Citations by year
- 2026: 159 · 2025: 188 · 2024: 185 · 2023: 169 · 2022: 176 · 2021: 196 · 2020: 186 · 2019: 138 · 2018: 125 · 2017: 100 · 2016: 102 · 2015: 88 · 2014: 59 · 2013: 3 · 2012: 3
- FWCI
- 37.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (5p01ca078378-15)
- National Heart, Lung, and Blood Institute (R01HL082945)
- National Human Genome Research Institute (RL1HG004671)
- National Cancer Institute (P01-CA078378, P50CA100707, P01CA108631, P01CA155258)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- lenalidomide, multiple myeloma, IKZF1, IKZF3, selective protein degradation, E3 ubiquitin ligase, ubiquitination, mechanism of action, IL-2 production, T cells, transcription factors
- MeSH terms
- Lenalidomide, Antineoplastic Agents, Humans, Interleukin-2, Multiple Myeloma, T-Lymphocytes, Thalidomide, Cell Line, Tumor, Ikaros Transcription Factor, Ubiquitination, HEK293 Cells, Proteolysis
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