EZM2302 / GSK, Ipsen - LARVOL DELTA

CARM1 in human cancer: a multifunctional epigenetic node driving tumor plasticity and therapeutic vulnerability. (PubMed, Biochim Biophys Acta Rev Cancer) - "Catalytic inhibitors such as TP-064 and EZM2302 differ in binding mode and substrate coverage, whereas emerging degraders can remove scaffolding functions but remain constrained by delivery, E3-ligase heterogeneity, pharmacokinetics, and therapeutic-window uncertainties. Biomarker-guided synthetic-lethal and immunotherapy combinations may therefore offer the most tractable route to clinical translation. This framework positions CARM1 as a context-conditioned signal-to-chromatin translator rather than a uniformly druggable oncogene."

Journal • Review • Gene Therapies • Oncology • Targeted Protein Degradation

Context-specific applications of CARM1 inhibitors: functional profiles of EZM2302 and TP-064. (PubMed, Mol Med) - "Our study reveals fundamental mechanistic differences between TP-064 and EZM2302 in regulating CARM1 substrates and downstream pathways. This substrate-selective inhibition has important implications for experimental design and therapeutic development, underscoring the need for context-specific selection of CARM1 inhibitors in both basic research and precision medicine."

Journal • GAPDH

Development of a Selective and Potent PRMT4 PROTAC Degrader with Efficacy against Multiple Myeloma in Vitro and in Vivo. (PubMed, J Med Chem) - "Importantly, in vivo studies showed that C199 had a relatively long half-life (10.10 h versus 4.89 h for EZM2302) and demonstrated strong antitumor activity (TGI = 78% versus 49% for EZM2302) without significant toxicity even at high doses. These findings provide the first evidence that PRMT4-targeted PROTAC degrader can exhibit therapeutic effects in vivo, offering a promising new therapeutic strategy for MM."

Journal • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • Von Hippel-Lindau Syndrome

Dual CARM1-and IKZF3-targeting: A novel approach to multiple myeloma therapy synergy between CARM1 inhibition and IMiDs. (PubMed, Mol Ther Oncol) - "Rational design of a new molecule, 074, which consists of a CARM1 inhibitor linked to the IMiD pomalidomide, was carried out and treatment with this agent led to more potent killing of MM cells than either the CARM1 inhibitor or the IMiD as single agents. Importantly, 074 was able to override IMiD resistance. Taken together, our results demonstrate that dual CARM1/IKZF3-targeting agents represent a promising novel therapeutic strategy for MM and IMiD-resistant disease."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • IKZF3 • MYC

A CARM1 Inhibitor Potently Suppresses Breast Cancer Both In Vitro and In Vivo. (PubMed, J Med Chem) - "We herein discovered a CARM1 inhibitor, iCARM1, that showed better specificity and activity toward CARM1 compared to the known CARM1 inhibitors, EZM2302 and TP-064. The combination of iCARM1 with either endocrine therapy drugs or etoposide demonstrated synergistic effects in inhibiting the growth of breast tumors. In summary, targeting CARM1 by iCARM1 effectively suppresses breast tumor growth, offering a promising therapeutic approach for managing breast cancers in clinical settings."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor

Carm1 Inhibition Potentiates Irradiation-Induced Antitumor Immunity via Tumor Intrinsic STING Pathway Activation. (PubMed, Int J Radiat Oncol Biol Phys) - "In this study, we identified that Carm1 ablation in tumor cells could promote irradiation-induced antitumor immunity through tumor cell intrinsic STING pathway activation. Mechanically, Carm1 deficiency directly activated the cGAS-STING pathway by interacting with TBK1 and increased mtDNA accumulation in cytoplasm by inhibiting autophagy. These findings provided new strategies for targeting Carm1 to boost the efficacy of radiotherapy."

IO biomarker • Journal • Oncology

Carm1 Inhibition Potentiates Irradiation-Induced Antitumor Immunity via Tumor Intrinsic STING Pathway Activation (ASTRO 2023) - "Finally, Carm1 inhibitor EZM2302 was applied in combination with radiotherapy in vitro , and it’s indicated that combination therapy resulted in intensive anti-tumor immunity and prominent abscopal effects... In this study, we identified that Carm1 ablation in tumor cells could promote irradiation-induced antitumor immunity through tumor cell intrinsic STING pathway activation. Mechanically, Carm1 deficiency directly activated the cGAS-STING pathway by interacting with TBK1 and increased mtDNA accumulation in cytoplasm by inhibiting autophagy. These findings provided new strategies for targeting Carm1 to boost the efficacy of radiotherapy."

IO biomarker • Oncology

Impact of short-term, pharmacological CARM1 inhibition on skeletal muscle mass, function, and atrophy in mice. (PubMed, Am J Physiol Endocrinol Metab) - "Adult mice (n = 10-11/sex) were treated with either a CARM1 inhibitor (150 mg/kg EZM2302; EZM) or vehicle (Veh) via oral gavage for 11-13 days and muscle mass, function, and exercise capacity were assessed...Furthermore, skeletal muscle atrophy and autophagy gene expression programs were elevated in response to DEN independent of CARM1 suppression. Collectively, these results suggest that short-term, pharmacological CARM1 inhibition in adult animals affects muscle performance in a sex-specific manner but does not impact the maintenance and remodeling of skeletal muscle mass during conditions of neurogenic muscle atrophy."

Journal • Preclinical • Muscular Atrophy

Characterization of CARM1 Inhibition in Skeletal Muscle. (PubMed, FASEB J) - "Mice were treated with either a CARM1 inhibitor (150 mg/kg EZM2302; Epizyme, Inc.) or vehicle via oral gavage BID for 2, 4, or 8 days. Furthermore, CARM1 inhibitor treatment may affect muscle performance with males being more sensitive to the functional outcomes of CARM1 suppression than females. Future work in our laboratory will examine the mechanisms and functional consequences of sex-based differences in CARM1 biology within skeletal muscle."

Journal • PABPC1

The circular RNA circHMGB2 drives immunosuppression and anti-PD-1 resistance in lung adenocarcinomas and squamous cell carcinomas via the miR-181a-5p/CARM1 axis. (PubMed, Mol Cancer) - "circHMGB2 overexpression promotes the LUAD and LUSC progression mainly by reshaping the tumor microenvironment and regulating anti-PD-1 resistance in the LUAD and LUSC patients. This study provides a new strategy for the LUAD and LUSC treatment."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • MIR181A1