eragidomide (CC-90009) / BMS - LARVOL DELTA

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 Malignancies • Leukemia • Lymphoma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • CD123 • CRBN • GSPT1 • IL3RA

Single-Cell Lineage Tracing Uncovers Resistance Signatures and Sensitizing Strategies to FLT3 Inhibitors in Acute Myeloid Leukemia. (PubMed, Cancer Res) - "Here, we applied our recently developed single-cell lineage tracing method ReSisTrace to identify cells that are intrinsically resistant or sensitive to the FLT3 inhibitors midostaurin and quizartinib in AML with FLT3-ITD mutations...In addition, in an FLT3-ITD-positive AML patient-derived xenograft (PDX) mouse model, the CC-90009 and quizartinib combination showed significantly higher anti-tumor efficacy and prolonged overall survival compared to either treatment alone...Vistusertib (mTOR inhibitor), linsitinib (IGF1R and insulin receptor inhibitor), and meisoindigo (IGF1R and Src family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to sensitize FLT3-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the ability of ReSisTrace to unveil pre-existing transcriptional features of treatment vulnerability in hematological cancers and elucidate..."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • FLT3 • GSPT1 • IR

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

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

Novel eRF3a degrader enhances gentamicin-induced premature termination codon readthrough in epidermolysis bullosa. (PubMed, Mol Ther Nucleic Acids) - "Finally, C7 and laminin 332 induced by CC-90009/gentamicin localized to the dermal-epidermal junction in RDEB and JEB skin equivalents. Therefore, CC-90009/gentamicin may present a novel and safe treatment option for RDEB, JEB, and other inherited skin diseases arising from nonsense mutations."

Journal • Dermatology • Genetic Disorders • COL7A1 • GSPT1 • LAMA3 • LAMC2

Discovery of non-aminoglycoside small molecules that enhance eRF3 degrader-induced translational readthrough of CFTR nonsense mutations (NACFC 2025) - "To address this issue, following a high-throughput screen (HTS) in the presence of the eRF3 degrader CC-90009, we applied medicinal chemistry optimization to identify small molecules (non-aminoglycosides, eRF3 degrader enhancers) that exhibit an additive or synergistic effect with SRI-47749, thereby effectively improving translational RT and restoring CFTR function...Addition of CFTR correctors elexacaftor and tezacaftor (ET) to SRI-50308 and SRI-47749 further improved CFTR protein expression and function... SRI-50308 is a novel non-aminoglycoside that enhances the translational readthrough induced by eRF3 degraders such as SRI-47749, thereby restoring substantial CFTR function from PTC alleles in primary cells. Further evaluation of these novel "eRF3 degrader enhancers" on the readthrough CFTR nonsense variants is a promising approach to multi-drug readthrough therapy for nonsense suppression."

CFTR

Targeted eRF3a degradation amplifies nonsense mutation readthrough in a CF murine model (NACFC 2025) - "Organoids treated with G418 (readthrough agent) and VX-445 and VX-661 (CFTR modulators) for 24 hrs with either SMG1i (NMD inhibitor), CC-90009 (0.01 μM), or SJ6986 (0.05 μM) produced the following FIS area under the curve (AUC) results respectively: 1970 ± 33, 2730 ± 36, and 2810 ± 77 (% swelling x time). The intestinal organoids effectively responded to the CRBN modulators producing robust CFTR function as measured by FIS. The lack of NMD inhibition needed in combination with these modulators is exciting as NMD inhibition by SMG1i is toxic and difficult to overcome in therapy development. We plan to treat primary airway cells from the same mice to verify that restoration of CFTR function can be achieved in the airway as well when using CRBN modulators."

Preclinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • Targeted Protein Degradation • CRBN • GSPT1

Genome-Wide KO Screen (GWS) to uncover genes promoting Premature Termination Codon readthrough (NACFC 2025) - "Cas9 expression was then induced, and cells treated with either G418 or CC-90009/ Eragidomide... A CRISPR-based GWS using our RT reporter cell system, combined with GFP+ phenotypic selection, identified genes that promote PTC readthrough. However, none outperformed eRF1 or eRF3a RT activity, or showed efficacy in the native CFTR genomic context. RT efficiency depends on CFTR mRNA levels and compete with NMD."

Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Respiratory Diseases • CFTR • GSPT1

Elucidating the mechanism of ENaC activity reduction by CC-90009 (NACFC 2025) - "These data demonstrate that CC-90009 reduces ENaC activity in HAECs in a cereblon-dependent, eRF3a-independent fashion. This suggests that CC-90009 leverages the CRL4CRBN E3 ubiquitin ligase to cause the ubiquitination and subsequent proteasomal degradation of an unknown neosubstrate involved in regulating ENaC activity. While additional experimentation is required to identify the exact target in this molecular pathway from the pool of candidate proteins identified via LCMS/MS, this work provides mechanistic insight into a potentially novel, druggable pathway of ENaC activity regulation."

Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • CRBN • GSPT1

Characterization of mTOR inhibitors for nonsense suppression of CFTR PTC variants (NACFC 2025) - " Combining aminoglycosides (G418, ELX-02) with eRF3a degrader CC-90009 resulted in the readthrough of native CFTR R1162X, achieving significant levels of full-length functional CFTR protein. Translational readthrough modulator screens have identified ribosome-binding antibiotics and eRF degraders as facilitators of PTC readthrough. Chemically diverse HTS hits likely have other mechanisms of action. A better understanding of the biological processes of nonsense suppression is crucial for developing therapeutic strategies to manage diseases caused by PTCs."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR • EIF2A • EIF2S1 • EIF4EBP1 • GSPT1 • RPS6

MRT-2359 - a novel molecular glue degrader of eRF3a induces readthrough of CFTR PTC variants (NACFC 2025) - "When combined with AGs G418 or ELX-02, MRT-2359 exhibited synergistic effects that further promoted functional readthrough in G542X, R1162X, and W1282X models, outperforming CC-90009... MRT-2359, alone or in combination with readthrough-promoting AGs, partially restores CFTR function for multiple CFTR PTC variants. These findings support further explorations of eRF3a as a therapeutic target for treating CF caused by nonsense variants."

Cystic Fibrosis • Genetic Disorders • Genito-urinary Cancer • Immunology • Prostate Cancer • Respiratory Diseases • Solid Tumor • Targeted Protein Degradation • CFTR • GSPT1

CC-90009, a modulator of Cereblon E3 ligase, restores W1282X and G542X CFTR nonsense variants in rectal organoids (NACFC 2025) - "Furthermore, the combination with the aminoglycosides G418 or ELX-02 but not with PTC124 further enhances their mutual effects, remarkably increasing the PTC readthrough response. In conclusion, the eRF3a degrader CC-90009, alone or combined with other compounds, could represent a promising therapeutic approach to rescue CFTR nonsense variants. Additional candidate read-through molecules are currently under study using our intestinal organoid-based screening and validation platform."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • Targeted Protein Degradation • CFTR • CRBN • GSPT1

Investigating the combinatorial effects of ACE-tRNAs and small molecules to suppress CF-causing nonsense mutations (NACFC 2025) - "Figure 1 (abstract 279): Simultaneous AZD-7648 and UbVa treatment enhances gene insertion in primary ABCs using the dual-vector strategy...Additionally, several small molecules with differing mechanisms of actions have been shown to readthrough PTCs, such as G418, PTC124, SRI-41315 and CC-90009... Currently, experiments to determine the optimal ACE-tRNA + small molecule combinations are being performed."

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

Therapeutic Opportunities in Overcoming Premature Termination Codons in Epidermolysis Bullosa via Translational Readthrough. (PubMed, Cells) - "Preclinical and clinical studies with gentamicin have demonstrated restored type VII collagen and laminin-332 expression, leading to measurable clinical improvements. Parallel development of novel compounds-including aminoglycoside analogs (e.g., ELX-02), translation termination factor degraders (e.g., CC-90009, SRI-41315, SJ6986), tRNA post-transcriptional inhibitors (e.g., 2,6-diaminopurine, NV848), and nucleoside analogs (e.g., clitocine)-has expanded the therapeutic pipeline. Although challenges remain regarding toxicity, codon specificity, and variable protein restoration thresholds, continued advances in molecular targeting and combination therapies offer the potential to establish readthrough therapies as localized or systemic treatments addressing both cutaneous and extracutaneous disease manifestations in EB."

Journal • Review

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 Malignancies • Leukemia • Oncology • Solid Tumor • ATF3 • ATF4 • BCL2 • CD34 • GSPT1 • GYPA • MYC • TFRC • TP53

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

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

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