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Cited by 229Protein Degradation and InhibitorsAcute Myeloid Leukemia ResearchUbiquitin and proteasome pathways

CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells

Open access
Surka, Christine, Jin, Liqing, Mbong, Nathan, Lu, Chin-Chun, Jang, In Sock, Rychak, Emily, Mendy, Derek, Clayton, Thomas +21 more·2021·Blood
DOI 10.1182/blood.2020008676PMC PMC8215192
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Abstract

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982).

AI snapshot

Written from the paper’s full text.

TL;DR

CC-90009 is a first-in-class GSPT1-selective cereblon E3 ligase modulator that induces GSPT1 degradation, acute AML apoptosis, and elimination of leukemia stem cells. Its activity is modulated by ILF2/ILF3-dependent CRBN splicing, mTOR signaling, and the GCN1/GCN2/ATF4 integrated stress response.

Key findings

  • CC-90009 selectively degraded GSPT1 with minimal effect on the rest of the proteome and did not degrade IKZF1, HBS1L, or CK1a; the GSPT1 G575N mutation conferred complete resistance, and GSPT1 stabilization blocked the anti-AML response, indicating GSPT1 degradation is necessary and sufficient for activity.
  • In 35 primary AML xenografts, 24 responders showed 52% to 100% reduction of CD45+CD33+ AML cells in injected femur and 62% to 99% in noninjected bones; 8 partial responders had 20% to 60% relative reduction, and 3 nonresponders had <20% relative reduction.
  • In vitro, 100 nM CC-90009 reduced GSPT1 by >70% in 9 of 23 patient samples, 50% to 70% in 8, and <50% in 6; LSC frequency decreased ninefold in representative sample AML3, 3 of 12 tested samples had statistically significant LSC frequency decreases, and 12 of 27 high-LSC17 cases showed >90% depletion of leukemic graft.
  • A genome-wide CRISPR-Cas9 screen identified ILF2/ILF3 as regulators of CRBN alternative splicing, TSC1/TSC2 loss as mTOR-mediated protection against GSPT1 degradation, and GCN1/GCN2/ATF4 as mediators of CC-90009-induced integrated stress response and apoptosis.

Methods

  • Biochemical, structural, and molecular characterization included cocrystallization of CC-90009 with GSPT1, DDB1, and cereblon; immunoblotting; proteomics; and binding/degradation assays.
  • A genome-wide CRISPR-Cas9 screen was performed in U937 cells using a pooled lentiviral library targeting ~19,000 protein-encoding genes, with CC-90009 or DMSO treatment, followed by RNA-sequencing and quantitative RT-PCR for CRBN splicing and CRISPR competition assays.
  • Primary AML samples were tested in vitro (23 samples) and in vivo by xenografting 35 samples in NOD.SCID mice, with serial limiting dilution assays in secondary recipients and LSC17 scoring.

Limitations

  • The paper states heterogeneous responses among patient samples in apoptosis, differentiation, and retention of primitive CD34+ cells; a few samples showed increased LSC frequency with CC-90009 treatment, which may relate to distinct GSPT1 levels or LSC subclones, and clonal tracking studies in future clinical trials are needed.
  • The paper notes OCI-AML3 resistance is associated with insufficient GSPT1 degradation, and the CRISPR screen was performed in U937 cells, so generalizability across all AML contexts is not fully established.
  • The reported data are preclinical; the abstract states the findings give insight into further assessment of clinical utility, with trials registered as NCT02848001 and NCT04336982, but no clinical efficacy outcomes are reported in this paper.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1182/blood.2020008676

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 5 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The CRISPR screen revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators.

    “The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators.”
    Quote in the paperSubstantial claim
  • Findingown data

    CC-90009 coopts the CRL4 CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation.

    “Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4 CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation.”
    Quote in the paperSubstantial claim
  • Findingown data

    Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009.

    “Knockout of ILF2/ ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009.”
    Quote in the paperSubstantial claim
  • Findingown data

    Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation.

    “Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation.”
    Quote in the paperSubstantial claim
  • Findingreasoning

    GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells.

    “On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells.”
    Quote in the paperSubstantial claim
  • May combine two claims. 26
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Findingown data

    CC-90009 demonstrated potent antiproliferative activity in 10 of 11 AML cell lines, with much less effect on the cell viability of PBMCs and THLE-2.

    “We identified a novel CELMoD agent, CC-90009, which demonstrated potent antiproliferative activity in 10 of 11 cell lines (Figure 1A-B; supplemental Figure 1A), with much less effect on the cell viability of PBMCs and THLE-2.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Normal PBMCs, THLE-2 cells, and cord blood CD34+ cells represent normal tissues for assessing CC-90009 toxicity.

  • May combine two claims.

    Findingown data

    Depletion of GSPT1 by CC-90009 rapidly induces AML apoptosis, reducing leukemia engraftment and LSCs in primary patient xenografting of 35 independent AML samples, including those with adverse risk features.

    “Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Effective treatment options for patients with poor-risk cytogenetic features or relapsed/refractory AML are still needed.

  • May combine two claims.

    Findingown data

    CC-90009 selectively degrades GSPT1, resulting in acute AML apoptosis and elimination of disease-driving LSCs.

    “CC-90009 selectively degrades GSPT1, resulting in acute AML apoptosis and elimination of diseasedriving LSCs.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Effective treatment options for patients with poor-risk cytogenetic features or relapsed/refractory AML are still needed.

  • May combine two claims.

    Findingown data

    ILF3 knockout reduced the mRNA level of CRBN-201 and CRBN-203 and increased the level of splicing variant CRBN-213, which is composed of exons 1 through 4 and a cryptic exon 5 containing a premature stop codon.

    “ILF3 knockout reduced the mRNA level of CRBN-201 and CRBN-203 and increased the level of splicing variant CRBN-213, which is composed of exons 1 through 4 and a cryptic exon 5 containing a premature stop codon (Figure 3F; supplemental Figure 4F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rapid and highly efficient loss of viable leukemic cells was detected in 8 of 9 patient samples at 48 hours posttreatment with CC-90009, and nearly all leukemic cells were eliminated within 96 hours.

    “Rapid and highly efficient loss of viable leukemic cells was detected in 8 of 9 patient samples at 48 hours posttreatment with CC-90009 (Figure 1C), and nearly all leukemic cells were eliminated within 96 hours (supplemental Figure 1E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CC-90009 treatment triggered rapid phosphorylation of eIF2α; accumulation of ATF4 and its transcriptional targets DDIT4, CHOP, and ATF3; and subsequent induction of apoptosis.

    “Indeed, CC-90009 treatment triggered the rapid phosphorylation of eIF2a; accumulation of ATF4 and its transcriptional targets DDIT4, CHOP, and ATF3; and subsequent induction of apoptosis (Figure 5E; supplemental Figure 6H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CC-90009 promoted the binding of cereblon to GSPT1 but not IKZF1, whereas lenalidomide exhibited binding selectivity toward IKZF1 over GSPT1.

    “Moreover, CC-90009 promoted the binding of cereblon to GSPT1 but not IKZF1 when added directly into the binding assays performed with cell extracts, whereas lenalidomide exhibited binding selectivity toward IKZF1 over GSPT1 (supplemental Figure 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ILF3 loss drastically reduced cereblon expression, and hence CC-90009-induced GSPT1 degradation and growth inhibition.

    “ILF3 loss drastically reduced cereblon expression, and hence CC-90009induced GSPT1 degradation and growth inhibition (Figure 3B,D; supplemental Figure 4C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Immunoblotting confirmed the specific degradation of GSPT1 but not other known CC-885 neosubstrates including IKZF1, HBS1L, and CK1a.

    “immunoblotting confirmed the specific degradation of GSPT1 but not other known CC-885 neosubstrates including IKZF1, HBS1L, and CK1a (Figure 1F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CC-90009 treatment led to cell growth arrest and significantly affected the sgRNA distribution as compared with DMSO control in a genome-wide CRISPR screen.

    “As expected, CC-90009 treatment led to cell growth arrest and significantly affected the sgRNA distribution as compared with DMSO control (Figure 2B; supplemental Figure 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GCN2 knockout inhibited eIF2α phosphorylation, induction of ATF4 and its target gene DDIT4, and caspase-3 cleavage in U937 cells treated with CC-90009.

    “GCN2 knockout inhibited eIF2a phosphorylation, induction of ATF4 and its target gene DDIT4, and caspase-3 cleavage in U937 cells treated with CC-90009 (Figure 5E-F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CC-90009-induced GSPT1 downregulation can be blocked by proteasomal inhibition with bortezomib, or inactivation of the CRL4 CRBN complex with MLN4924 or CRBN knockout.

    “The CC-90009-induced GSPT1 downregulation can be blocked by proteasomal inhibition with bortezomib, or inactivation of the CRL4 CRBN complex with MLN4924 or CRBN knockout (Figure 1F-G; supplemental Figure 1G-H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CC-90009 treatment reduced GSPT1 protein abundance with minimal effect on the rest of the proteome in KG-1 AML cells.

    “CC-90009 treatment reduced the GSPT1 protein abundance with minimal effect on the rest of the proteome (Figure 1E), and immunoblotting confirmed the specific degradation of GSPT1 but not other known CC-885 neosubstrates including IKZF1, HBS1L, and CK1a (Figure 1F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CC-90009 resistance in OCI-AML3 is associated with insufficient GSPT1 degradation, and RNA interference-mediated partial GSPT1 knockdown restored CC-90009 activity.

    “CC-90009 resistance in OCI-AML3 is associated with insufficient GSPT1 degradation, and RNA interference-mediated partial GSPT1 knockdown restored CC-90009 activity (supplemental Figure 1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GSPT1 degradation activates the GCN1/GCN2/eIF2α/ATF4 axis of the ISR, with concomitant induction of acute apoptosis in AML.

    “GSPT1 degradation activates the GCN1/GCN2/eIF2a/ATF4 axis of the ISR, with concomitant induction of acute apoptosis in AML.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    mTORC1 hyperactivation owing to loss of TSC1 or TSC2 significantly blocked CC-90009-induced GSPT1 recruitment to cereblon, and hence diminished GSPT1 degradation and CC-90009 sensitivity in AML.

    “We showed that mTORC1 hyperactivation owing to loss of TSC1 or TSC2 significantly blocked the CC-90009-induced GSPT1 recruitment to cereblon, and hence diminished GSPT1 degradation and CC-90009 sensitivity in AML.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    78 genes were significantly enriched by CC-90009 treatment (log2 FC > 2 and FDR < 0.05).

    “Scatter plot of 78 genes significantly enriched by CC-90009 (log 2 FC .2 and FDR ,0.05).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CC-90009 reduces leukemic engraftment in mice transplanted with de novo or secondary/relapsed AML, normal or abnormal cytogenetics, MRC adverse or intermediate risk group, and high or low LSC17 scores.

    “Relative reduction in leukemic engraftment in mice treated with CC-90009 compared with controls, and transplanted with de novo or secondary or relapsed AML, normal or abnormal cytogenetics, MRC adverse or intermediate risk group, and high or low LS17 scores.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CC-90009 treatment reduces GSPT1 in AML patient samples, with reduction categories at 100 nM.

    “Lines in black, cyan, and red represent samples with .70%,50% to 70%, and ,50% GSPT1 reduction, respectively, at the 100-nM treatment dose.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    GSPT1 stabilization completely inhibited the response to CC-90009, ruling out the participation of other substrates in the anti-AML effect of CC-90009.

    “GSPT1 stabilization completely inhibited the response to CC-90009 (Figure 1L; supplemental Figure 2E-F), ruling out the participation of other substrates in the anti-AML effect of CC-90009.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    GSPT1 degradation is both necessary and sufficient to account for the anti-AML activity of CC-90009.

    “Thus, GSPT1 degradation is both necessary and sufficient to account for the anti-AML activity of CC-90009.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Overall, CC-90009 can target LSCs in the AML xenograft model, albeit with heterogeneous responses among AML cases.

    “Overall, these data indicate that CC-90009 can target LSCs in the AML xenograft model, albeit with heterogeneous responses among AML cases.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Selective degradation of just the intended target optimizes the therapeutic index and overcomes toxicities associated with earlier, more promiscuous, cereblon modulators and provides a roadmap for the design of next-generation CELMoD agents.

    “Beyond CC-90009, selective degradation of just the intended target optimizes the therapeutic index and overcomes toxicities associated with earlier, more promiscuous, cereblon modulators and provides a roadmap for the design of the next-generation CELMoD agents.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Differences in response among patient samples may be related to distinct GSPT1 levels that exist between patients or between LSC subclones within individual patients.

    “These differences in response among patient samples may be related to distinct GSPT1 levels that exist between patients or even between LSC subclones within individual patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In the context of dysregulated protein translation termination, the GCN2-mediated ISR upon GSPT1 degradation promotes acute apoptotic cell death in AML cell lines and patient blasts with minimal effect on normal PBMC, THLEs, or T-lymphocytes, indicative of an exclusive vulnerability to GSPT1 loss in AML.

    “In the context of dysregulated protein translation termination, the GCN2-mediated ISR upon GSPT1 degradation promotes acute apoptotic cell death in AML cell lines and patient blasts with minimal effect on normal PBMC, THLEs, or T-lymphocytes indicative of an exclusive vulnerability to GSPT1 loss in AML.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Normal PBMCs, THLE-2 cells, and cord blood CD34+ cells represent normal tissues for assessing CC-90009 toxicity.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Effective targeting of leukemic blasts and LSCs in AML samples with poorer prognosis supports further development of CC-90009 in clinical trials as a novel agent for patients with refractory/relapsed AML.

    “Such effective targeting of leukemic blasts and LSCs in AML samples with poorer prognosis supports further development of CC-90009 in clinical trials as a novel agent for patients with refractory/relapsed AML.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Preclinical activity of CC-90009 against AML blasts and LSCs in patient samples and xenograft models predicts clinical efficacy in patients with refractory/relapsed AML.

  • May combine two claims.

    Interpretationown data

    Ablation of DDIT4 significantly reduced the response to CC-90009 and largely mimicked the gene knockout effect of GCN1, GCN2, and ATF4, strongly suggesting that the GCN2-mediated anti-AML activity of CC-90009 is mainly exerted by REDD1 among all the target genes transactivated by ATF4.

    “Ablation of DDIT4(REDD1) significantly reduced the response to CC-90009 and largely mimicked the gene knockout effect of GCN1, GCN2, and ATF4, strongly suggesting that the GCN2-mediated anti-AML activity of CC-90009 is mainly exerted by REDD1 among all the target genes transactivated by ATF4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The alternative splicing of CRBN mRNA transcripts controlled by the ILF2/ILF3 complex was detected in all tested cell lines regardless of cell type or tissue of origin, suggesting that ILF2 or ILF3 loss should attenuate the response to all cereblon modulating agents.

    “For example, the alternative splicing of CRBN mRNA transcripts controlled by the ILF2/ ILF3 complex was detected in all tested cell lines regardless of cell type or tissue of origin (data not shown), suggesting that ILF2 or ILF3 loss should attenuate the response to all cereblon modulating agents.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Multiple sgRNAs targeting each top-ranked gene were significantly enriched by CC-90009, strongly supporting the on-target gene knockout effect.

    “Note that in panels E and F, multiple sgRNAs targeting each of these top-ranked genes were significantly enriched by CC-90009, strongly supporting the on-target gene knockout effect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Results in all figure panels are representative of 3 biological replicates.

    “Result shown in all figure panels is representative of 3 biological replicates.”
    Quote in the paperNot a substantial claim
30 of 30

  • The paper relies on this without support.

    Effective treatment options for patients with poor-risk cytogenetic features or relapsed/refractory AML are still needed.

    “effective options for patients with poor risk cytogenetic features, or relapsed and refractory disease are still needed.”

  • The paper relies on this without support.

    Normal PBMCs, THLE-2 cells, and cord blood CD34+ cells represent normal tissues for assessing CC-90009 toxicity.

    “with much less effect on the cell viability of PBMCs and THLE-2.”
    “CC-90009 had lesser inhibitory effect on normal cord blood CD34 1 primitive cells in the xenograft than AML CD34 1 cells”

  • The paper relies on this without support.

    Preclinical activity of CC-90009 against AML blasts and LSCs in patient samples and xenograft models predicts clinical efficacy in patients with refractory/relapsed AML.

    “Such effective targeting of leukemic blasts and LSCs in AML samples with poorer prognosis supports further development of CC-90009 in clinical trials as a novel agent for patients with refractory/relapsed AML.”

  • The paper relies on this without support.

    LSC frequency measured by limiting dilution secondary transplantation in mice reflects the disease-driving LSC population in patients.

    “LSC frequency in CC-90009-or control-treated mice determined by secondary transplantation at limiting doses for representative sample AML3 (left) and summary graph showing fold change in LSC frequency for all samples tested by limiting dilution analysis (right).”
4 of 4

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?

  • Several rationally optimized CELMoDs are now in clinical trials for both solid and haematological malignancies.

    “Several of these rationally optimized celMoDs are now in clinical trials for both solid and haematological malignancies, demonstrating the potential for rational compound optimization”

    From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Surka et al. 2021

    The Introduction names several novel CELMoDs developed to treat haematological malignancies, and the Discussion describes CC-90009 as a route to designing improved agents. Neither passage establishes that several are already in clinical trials or that those trials cover solid malignancies; the Discussion instead calls for further clinical development of CC-90009. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Further refinement of GSPT1-targeting compounds has resulted in three potent molecules: CC-90009, BTX-1188 and MRT-2359.

    “For gSPt1 in particular, further refinement of these compounds has resulted in three potent gSPt1-targeting molecules: cc-90009, BtX-1188and MRt-2359(Surka et al. 2021).”

    From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Surka et al. 2021

    The Introduction describes CC-90009 as a GSPT1-selective agent developed after CC-885, and the targeted-degradation section reports its GSPT1-directed activity. Our copy does not mention BTX-1188 or MRT-2359, so it does not support the claim that refinement resulted in all three named molecules. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Custom CELMoDs targeting GSPT1 have demonstrated potential across multiple malignancies.

    “custom celMoDs targeting gSPt1 have already demonstrated potential across multiple malignancies (Matyskiela et al. 2016;Surka et al. 2021)”

    From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Surka et al. 2021

    The Introduction and Discussion identify CC-90009 as a GSPT1-selective CELMoD and report preclinical activity across a wide range of AML samples. That supports its potential in AML, but this paper does not demonstrate potential across multiple malignancies; its reported efficacy is confined to AML. No page numbers were available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The discovery of CC-885 as a CRBN-dependent GSPT1 degrader was initially motivated by cancer cell line profiling studies.

    “The discovery of CC-885 as a CRBN-dependent GSPT1 degrader53 was likewise initially motivated by cancer cell line profiling studies, prompting the development of the clinical candidate CC-90009.168,169”

    From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [168]

  • Target identification and elucidation of the mechanism of action of degraders via functional genomics was initially mostly driven by pooled CRISPR/Cas9 screens with a positive selection readout based on cellular fitness.

    “Target identification and elucidation of the mechanism of action of degraders via functional genomics was initially mostly driven by pooled CRISPR/Cas9 screens with a positive selection readout based on cellular fitness (“drug resistance screens”).168,232,233”

    From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [168]

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.

  • Partial responder falls outside the stated reduction range at both sites

    Minor

    The text says partial responders had 20% to 60% relative reduction. Table 1 classifies patient 24 as a partial responder but reports 9% reduction in RF and 97% in BM-neither is in that range.

  • Two different counts of differentially expressed genes

    Minor

    The Results state that ILF3 loss affected expression of 645 genes, whereas the Figure 3 caption reports 791 significantly up- or downregulated genes at the gene level.

  • Claim of significant reduction at both sites conflicts with Table 1

    Minor

    The Results describe significant reductions in both RF and BM for the 24 responders. Table 1 nevertheless labels the BM result for responder patient 8 as NS and the RF result for responder patient 18 as NS.

3 of 3

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Authors
Surka, C., Jin, L., Mbong, N., Lu, C.-C., Jang, I. S., Rychak, E., Mendy, D., Clayton, T., Tindall, E., Hsu, C., Fontanillo, C., Tran, E., Contreras, A., Ng, S. W. K., Matyskiela, M., Wang, K., Chamberlain, P., Cathers, B., Carmichael, J., Hansen, J., Wang, J. C. Y., Minden, M. D., Fan, J., Pierce, D. W., Pourdehnad, M., Rolfe, M., Lopez-Girona, A., Dick, J. E., & Lu, G.
Affiliations
  • Bristol-Myers Squibb (United States) (US)
  • University Health Network (CA)
  • Bristol-Myers Squibb, San Diego, CA;
Corresponding author
  • Surka, Christine
  • Jin, Liqing
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2021-02-04
Volume
137
Issue
5
Pages
661-677
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2020008676
PMC
PMC8215192
OpenAlex
W3100577837
Cited by
229
References
58
Citations by year
2026: 40 · 2025: 60 · 2024: 41 · 2023: 36 · 2022: 31 · 2021: 19 · 2020: 1 · 2014: 1
FWCI
7.21
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Energy (-AC02-05CH11231, 05CH11231, DE AC02 05CH11231, GM124169, DE-AC02-)
  • Bristol-Myers Squibb
  • Government of Ontario
  • International Development Research Centre
  • National Institutes of Health (DE-AC02–05CH11231, 1s10od021832-01, P30-GM124169-01, GM124169)
  • Office of Science (DEAC02–05CH11231, AC02-05CH11231, DE-AC02)
  • Canadian Institutes of Health Research (DE-AC02-05CH11231, 154293, 89932)
  • National Institute of General Medical Sciences (DE-AC02-05CH11231, GM124169-01, GM124169, P30GM124169)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
cereblon E3 ligase modulator, GSPT1, acute myeloid leukemia, leukemia stem cells, proteasomal degradation, mTOR signaling, integrated stress response, apoptosis, drug repurposing
MeSH terms
Acetamides, Animals, Humans, Models, Molecular, Neoplasm Proteins, Peptide Termination Factors, Piperidones, Protein Conformation, Protein Processing, Post-Translational, Stress, Physiological, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Mice, SCID, Mice, Inbred NOD, U937 Cells, Xenograft Model Antitumor Assays, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proteasome Endopeptidase Complex, Adaptor Proteins, Signal Transducing, Nuclear Factor 90 Proteins, Mice, Nuclear Factor 45 Protein, Receptors, Interleukin-17, Isoindoles, Small Molecule Libraries, Ubiquitination, TOR Serine-Threonine Kinases, Molecular Targeted Therapy, Proteolysis, CRISPR-Cas Systems

About these checks

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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