eragidomide (CC-90009) / BMS - LARVOL DELTA

Small molecules acting as eRF degraders differently rescue G542X and W1282X-CFTR function (ECFS 2025) - " 16HBE14o- cells with the G542X-CFTR mutation were treated for 24 h with different drug combinations containing CC-90009 (0.1 M) or SRI-41315 (15 M) with/without VX-809 (1 M), and ELX-02 (200 M), as a RT agent, or SMG1i (1 M), as a NMD inhibitor. The eRF3a degrader CC-90009 has a role in potentiating RT, since it is effective on G542X-CFTR in combination with ELX-02, while the eRF1 degrader SRI-41315 is particularly active on W1282X-CFTR together with SMG1i. These results suggest that eRF degraders have different involvement in RT and NMD mechanisms. This work was supported by: the Cystic Fibrosis Foundation (GALIET22I0), the Italian Cystic Fibrosis Foundation (FFC#9/2022 and GMRF#1/2024), and the Italian Ministry of Health (GR-2018-12367126)."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • GSPT1

TARGETING MUTANT TP53 ACUTE MYELOID LEUKEMIA THROUGH DISRUPTION OF MYC-GSPT1 AXIS (EHA 2025) - "GT19715 induced significantly greater SCR signals than CC-90009, a selective GSPT1 degrader, suggesting that dual MYC/GSPT1 degradation enhances SCR of MYC...Quiescent LSPCs exhibit sensitivity particularly to Venetoclax (Ven) (Zeng et al...GT19715 with Ven/5'-azacitidine (Aza) exhibited synergistic cell kill (Bliss index 67.67, P = 2.11e-10) in CD34+CD38- primary TP53 mutant AML LSCs (N = 7)... We identified a novel role of MYC in controlling translation termination and discovered that dual MYC/GSPT1 degradation by GT19715 profoundly synergized with Ven/Aza in TP53 mutant quiescent and proliferating AML stem/progenitor cells, resulting in substantial survival prolongation in TP53 mutant AML PDX models."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ATF3 • ATF4 • BCL2 • CD34 • GSPT1 • GYPA • MYC • TFRC • TP53

Drug target ID and binding site mapping in complex cellular environments using LiP-MS (AACR 2025) - "This workflow bypasses the need for protein purification, mitigating risks of protein truncation or misfolding.To evaluate LiP-MS' performance on molecular glue MoAs, we performed global target ID experiments using two well-characterized models: the cyclin K degraders CR8 and SR-4835 and the GSPT1 degraders MRT-2359 and Eragidomide...Applying HR-LiP, we mapped the binding site of the BRD4 inhibitor JQ1 on full-length BRD4, a large protein challenging to study via standard methods, using a mammalian transient overexpression system. Similarly, we located binding sites for EGFR inhibitors gefitinib and afatinib on the membrane-bound EGFR protein. Additionally, we pinpointed the SMER28 binding site on the hexameric ATPase VCP, an autophagy enhancer, demonstrating the method's applicability to large protein complexes.In conclusion, LiP-MS provides a versatile toolbox for identifying drug targets and mapping binding sites within complex cellular environments."

Oncology • BRD4 • CDK12 • CRBN • DDB1 • GSPT1

Seeking new glues - Toward an E3 ligase-agnostic molecular glue degrader identification platform (AACR 2025) - "Conversely, a key challenge with cell-based screening approaches is to understand the mechanism by which the target is degraded, relying on the identification of the ubiquitin ligase or adaptor protein that is mediating the effect of the compound.Here, we demonstrate the utility of our cell-based screening platform by developing degrader assays for two separate targets, Cyclin K and GSPT1, both therapeutically relevant for oncology, and with respective MGDs in clinical trials (CT7439 for cyclin K by Carrick Therapeutics, and MRT-2359 and Eragidomide from Monte Rosa Therapeutics and Cellgene/BMS, respectively).Further, to address the challenge of deconvoluting the mechanistic basis for monovalent degrader hits from cell-based assays, we have utilized limited proteolysis coupled with mass spectrometry (LiP-MS)...This methodology allows the identification of the proteins involved in mediating degradation of a target, such as a ubiquitin ligase recruited to a target via an..."

Oncology • GSPT1

TRX-214-1002, An antibody drug conjugate (ADC) targeting CD33 with a novel GSPT1 molecular glue for treatment of acute myeloid leukemia (AACR 2025) - "However, clinical development of GSPT1 MGDs, such as CC-885 and CC-90009, has been hampered by off-target toxicities...The in vitro and in vivo pharmacology of TRX-214-1002 were compared with ORM-6151 (another GSPT1 MG degrader-based CD33 ADC) and Mylotarg...Collectively, TRX-214-1002 highlighted the noticeable GSPT1 degradability and enhanced antileukemic activity, particularly in TP53 mutated and venetoclax-resistant AML cell lines, along with significant antitumor activity superior to competitor ADCs. Our preclinical data suggest that TRX-214-1002 has the high potential to provide a novel treatment strategy for CD33 positive relapse/refractory AML patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Oncology • Solid Tumor • ATF3 • ATF4 • CD33 • FLT3 • GSPT1 • TP53

PROTAC-Mediated GSPT1 Degradation Impairs the Expression of Fusion Genes in Acute Myeloid Leukemia. (PubMed, Cancers (Basel)) - "These findings suggest a new role of GSPT1 in regulating leukemic transcriptional networks and open a new therapeutic strategy to target leukemic fusion genes in pediatric AML patients."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Targeted Protein Degradation • CDK6 • CRBN • ERG • FUS • GSPT1 • RUNX1 • RUNX1T1

Discovery of a Potent and Selective GSPT1 Molecular Glue Degrader for the Treatment of Castration-Resistant Prostate Cancer. (PubMed, J Med Chem) - "Importantly, 7d exhibits superior efficacy compared to 1 (CC-90009) in degrading GSPT1 in 22Rv1 cells with a DC50 value of 19 nM...Mechanistically, via degradation of GSPT1, 7d downregulates CRPC-related oncogenes in 22Rv1 cells, including AR, AR-V7, PSA, and c-Myc. Thus, our work provides a novel GSPT1 selective degrader with potent effectiveness in targeting Myc-driven CRPC."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • CRBN • GSPT1 • MYC

Potent in Vitro and In Vivo Efficacy of Hdz-C123A, a GSPT1 Degrader-Antibody Conjugate Targeting CD123 in Acute Myeloid Leukemia (ASH 2024) - "In CD123-expressing cell lines, HDZ-C123A exhibited picomolar proliferative inhibition activity, which was 20-1000 times more potent than several GSPT1 degraders, including CC-90009, and showed robust activity in Mylotarg-resistant cell lines. Ex vivo experiments revealed a stronger potency of HDZ-C123A in AML patient-derived blasts compared to CC-90009 and venetoclax...Conclusions : In summary, CDG0501, as a potent GSPT1 degrader, demonstrates potential as a next-generation payload in preclinical studies. HDZ-C123A, constructed based on CDG0501, shows promising potential as a first-in-class CD123-targeting degrader-antibody conjugate for AML treatment."

Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • CD123 • CRBN • GSPT1 • IL3RA

Targeting Co-Regulatory Feedback Loop of MYC and GSPT1 By MYC/GSPT1 Dual Degradation Is Synthetic Lethal in Combination with Ven/Aza in TP53 Mutant Acute Myeloid Leukemia Stem and Progenitor Cells (ASH 2024) - "ASH 2022, 2023), induced significantly greater GFP signals than CC-90009, a selective GSPT1 CELMoD, suggesting that dual MYC/GSPT1 degradation enhances SCR on MYC gene...Quiescent LSPCs exhibit sensitivity particularly to Venetoclax (Ven) (Zeng et al...Indeed, the combinatorial treatment of GT19715 with Ven/5'-azacitidine (Aza) exhibited synergistic cell kill (Bliss index 67.67, P = 2.11e-10) in CD34+CD38- LSCs in primary TP53 mutant AML samples (N = 7)...The combinatorial treatment nearly eradicated these remaining AML cells in bone marrow samples in another ongoing PDX AML experiment (PDX824) carrying TP53 p.Y220C and p.G105fs, suggesting that the combinatorial approach of dual MYC/GSPT1 degradation with Ven/Aza can be an effective therapeutic approach for TP53 mutant AML. Conclusion : we identified a novel positive co-regulatory feedback loop between MYC and GSPT1, and found that dual MYC/GSPT1 degradation by GT19715 profoundly synergized in the induction of cell..."

Combination therapy • IO biomarker • Synthetic lethality • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • ATF3 • ATF4 • BCL2 • CD34 • CRBN • GSPT1 • GYPA • MYC • TFRC • TP53

Pharmacological rescue of CFTR premature termination codon (PTC) variants (NACFC 2024) - "Drugs that deplete translation termination release factors, such as eRF1 (depleted by SRI-41315) and eRF3 (degraded by CC-90009), are of particular interest...In G27X HNECs, we observed 17.1% WT CFTR rescue when elexacaftor/tezacaftor/ivacaftor (ETI) was added to the combination of CC-90009, G418, and SMG1i... CC-90009, G418, and SMG1i synergized to restore substantial G27X, G542X, R1158X, and W1282X CFTR activity but had negligible effect on E92X and Q890X CFTR. PTC CFTR-homozygous primary cells and cell lines are valuable tools to develop genotype-targeted, clinically relevant PTC readthrough and NMD-inhibiting agents."

BMI1

Rescue of CFTR nonsense mutations is enhanced under inflammatory stimuli (NACFC 2024) - "Cells were also treated in the last 24 hours with ELX-02 (200 µM) plus VX-809 (1 µM) with or without CC-90009 (0.1 µM). We found that cytokine-treated epithelia had an enhanced response to the triple compound combination containing the eRF3a degrader CC-90009. We are investigating the molecular basis of this behavior because the cytokine treatment may change expression of genes controlling protein synthesis, thus potentiating the effect of readthrough maneuvers."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • GSPT1 • IL17A • IL4 • TNFA

Screening for translational readthrough of CFTR R1162X leads to the identification of mammalian target of rapamycin inhibitors for nonsense suppression (NACFC 2024) - " Combining aminoglycosides (G418, ELX-02) with CC-90009 results in translational readthrough of native CFTR R1162X, achieving full-length CFTR protein levels equivalent to 20% of normal CFTR expression in parental 16HBE14o- cells. Screening a repurposing library is an attractive option to accelerate drug discovery for PwCF with CFTR nonsense variants. Further evaluation of the effect of mTOR inhibitors on the readthrough of CFTR nonsense variants may help reveal their therapeutic potential in nonsense suppression."

CFTR • GSPT1

CFTR premature termination codon readthrough can be enhanced by a transcript-specific antisense oligonucleotide approach (NACFC 2024) - "We also investigated whether combining ASOs with PTC modulators such as aminoglycosides (G418, ELX-02) and eRF degraders (SRI-41315, CC-90009) enhances PTC readthrough. This study presents a new approach for enhancing specific PTC readthrough in CFTR using ASOs that target a sequence near PTCs. This approach has the potential to safely increase the efficacy of current PTC modulators without exacerbating transcriptome-wide undesired effects."

CFTR

Identification of pre-sensitizing agents to FLT3 inhibitors in acute myeloid leukemia with lineage tracing (EACR 2024) - "The aim of our study was to unravel mechanisms behind primed resistance against FLT3 inhibitors driven by intrinsic transcriptional heterogeneity, and to identify novel pre-sensitizing agents to FLT3 inhibitors.Material and Methods To uncover pre-existing resistant states against FLT3 inhibitors midostaurin and quizartinib in an FLT3-ITD-positive MOLM-13 AML cell line, we employed our recently published single-cell lineage-tracing method ReSisTrace that combines genetic barcoding with single-cell RNA sequencing and utilizes the analysis of shared transcriptomic features of sister cells. Furthermore, vistusertib (mTOR inhibitor), linsitinib (IGF1R and insulin receptor inhibitor), and meisoindigo (IGF1R and Src family kinase inhibitor), all inhibiting pathways parallel or downstream of oncogenic FLT3 signaling, were predicted and validated to pre-sensitize AML cells to the FLT3 inhibitors.Conclusion Primed resistance against FLT3 inhibitors may be mediated by activation of..."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CRBN • ENO1 • FLT3 • GSPT1 • IR

A Safety and Efficacy Study of CC-90009 Combinations in Subjects With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=22 | Terminated | Sponsor: Celgene | Trial completion date: Oct 2025 ➔ Apr 2024 | Active, not recruiting ➔ Terminated; Business objectives have changed.

Combination therapy • Trial completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

A Dose-finding Study of CC-90009 in Subjects With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-risk Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=101 | Terminated | Sponsor: Celgene | Trial completion date: Jul 2025 ➔ Apr 2024 | Active, not recruiting ➔ Terminated; Trial terminated because of lack of efficacy in the short term acute phase.

Trial completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation

CC-90009 potentiates gentamicin-induced premature termination codon readthrough activity in epidermolysis bullosa (SID 2024) - No abstract available

Strategy for the optimization of read-through therapy for junctional epidermolysis bullosa with COL17A1 nonsense mutation. (PubMed, J Invest Dermatol) - "However, the amount of restored type XVII collagen (C17) in C17 deficient junctional epidermolysis bullosa (JEB-C17) keratinocytes was less than 1% relative to normal keratinocytes and was achieved only after high dose gentamicin treatment, which induced deep transcriptional changes...We developed TRID-C5 containing low dosage of aminoglycosides, CC-90009, NMDI-14, melatonin and apocynin that was able to induce about 20% of missing C17 without cell toxicity and effect on in vitro wound closure...Evaluation of this drug cocktail regarding its stability, penetration and efficacy as a topical treatment remains to be determined. TRID-C5 might represent an improved therapeutic strategy for JEB and for other genetic skin disorders."

Journal • Dermatology • Genetic Disorders • Inflammation • COL17A1

A Safety and Efficacy Study of CC-90009 Combinations in Subjects With Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: Celgene | Phase classification: P1/2 ➔ P1

Phase classification • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

A Safety and Efficacy Study of CC-90009 Combinations in Subjects With Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=22 | Active, not recruiting | Sponsor: Celgene | Phase classification: P1b ➔ P1/2 | N=76 ➔ 22

Combination therapy • Enrollment change • Phase classification • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Synthetic Lethal Interactions with IRAK4 Inhibition in Myeloid Malignancies (ASH 2023) - "In Phase-1 findings with a selective IRAK4 inhibitor (CA-4948; Curis Therapeutics), it was found that MDS and AML patients with splicing factor mutations responded best to monotherapy IRAK4 inhibition, although the overall response rate with monotherapy was modest...CC-90009 did not result in complete cell death up to concentrations of 10mM in both WT and IRAK4KO, suggesting that the selective sensitivity of IRAK4KO AML cells to CC-885 is not due to inhibition of GSPT1...These findings suggest that IRAK4 inhibition alters the pool of neosubstrates in AML cells for certain CELMoDs. Overall, our study demonstrates that IRAK4 is a therapeutic target in AML, but that combination therapies, such as with certain CELMoDs, will be necessary to achieve better clinical responses."

Synthetic lethality • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • ANXA5 • CASP3 • CRBN • GLI2 • GSPT1 • IKZF1 • IKZF2 • IKZF3 • IRAK4 • SF3B1 • U2AF1

Pharmacological induction of translational readthrough of nonsense mutations in the retinoblastoma (RB1) gene. (PubMed, PLoS One) - "Induction of full-length Rb protein was potentiated by the cereblon E3 ligase modulator CC-90009. These results suggest that pharmacological induction of translational readthrough could be a feasible strategy for therapeutic targeting of tumors with nonsense mutant RB1."

Journal • Astrocytoma • Brain Cancer • Breast Cancer • Eye Cancer • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • Targeted Protein Degradation • CRBN • RB1

Functional and RNA-level recovery of CFTR nonsense variants with NMD inhibition, readthrough, and ETI (NACFC 2023) - "Cells were treated with combinations of antisense oligonucleotides (ASOs) to NMD-critical transcripts (SMG1, SMG6, Upf3b), small-molecule inhibitors of NMD (NMDi14, Emetine), readthrough compounds (G418, ELOX-02, CC-90009, PTC-124), and elexacaftor-tezacaftor-ivacaftor (ETI). Our data suggest that therapeutic strategies for CF caused by nonsense variants resulting in NMD must consider RNA stability and compound toxicity. For some of these variants, including W1282X, CFTR function increases significantly with the addition of ETI after successful readthrough of stabilized RNA, but to treat those with nonsense variants that do not respond well to this protocol, such as R1162X, we must continue to pursue other innovative strategies such as tRNA suppression therapy and CRISPR-based approaches."

CFTR

Novel eRF3 degrader monotherapy induces translational readthrough of CFTR nonsense mutations at therapeutically relevant levels (NACFC 2023) - "CC-90009 rescued W1282X-CFTR func-tion to approximately 20% of wt levels and, when paired with G418, rescued G542X-CFTR function to approximately 50% of wt levels in Bmi-1/hTERT airway epithelial cell lines [1]...SRI-47749 combined with ELX-02 (53 μg/mL) and CFTR modulators (elexacaftor-tezacaftor-ivacaftor, 3 uM) increased forskolin-induced swelling in organoids from the same donors, reaching approximately 5% to 25% of the wt control. SRI-47749 is a novel compound that induces translational readthrough by degrading eRF3, which restores substantial CFTR function from PTC alleles in primary organoids. Further research for development of SRI-47749 as a monotherapeutic agent for people with CF with PTCs is ongoing."

Monotherapy • Targeted Protein Degradation • BMI1 • CFTR • CRBN • GSPT1

Synergistic effects on readthrough of G542X CFTR by combining eRF1 and eRF3 degraders (NACFC 2023) - "Thalidomide derivatives CC-885 and CC-90009 bridge an interaction between eRF3 and cereblon, an E3 ligase component. Combining eRF1 and eRF3 degraders can synergistically increase RT, although this level of RT is unlikely to rescue the amount of CFTR function (∼35% of wild type) needed to alleviate clinical symptoms. We are exploring strategies to increase the efficacy of eRF1 and eRF3 degraders and new ways of combining RT agents with different modes of action to maximize RT efficiency."

Targeted Protein Degradation • CRBN