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Background: PRMT5 is an epigenetic enzyme that catalyzes symmetric dimethylation of arginine substrates (SDMA), regulating multiple cell processes. The PRMT5-MTAP collateral vulnerability describes the accumulation of the metabolite methylthioadenosine (MTA) in tumor cells (as a result of the deletion of the MTAP gene), which acts as a natural endogenous partial inhibitor of PRMT5. This provides an opportunity to selectively inhibit PRMT5 in MTAP deleted tumors, which occurs in ~15% of all cancers. First generation PRMT5 inhibitors, which cannot discriminate between MTAP-proficient normal cells and MTAP-deficient tumor cells, have a narrow therapeutic index which may limit clinical efficacy due to on-target toxicity. MTAP-selective PRMT5 inhibitors spare MTAP-proficient normal cells, improving therapeutic index and clinical efficacy. We have developed a novel MTAP-selective PRMT5 inhibitor, AZ-PRMT5i-1, that selectively targets MTAP-deficient tumors and spares MTAP-proficient tissue. Methods: In vitro activity of AZ-PRMT5i-1 was profiled using six MTAP isogenic cell lines, as well as in a panel of 300 cancer cell lines. In vivo efficacy was assessed using three MTAP deleted models and hematological toxicity was addressed using a 3D human bone marrow model. Results: Using a MTAP CRISPR KO isogenic pair we demonstrate potent inhibition of SDMA in MTAP-null tumors with a 54-fold margin over the MTAP wildtype (WT) counterpart. MTAP differential activity was maintained in proliferation assays across a number of MTAP isogenic cell lines and in a panel of 300 cancer cell lines. AZ-PRMT5i-1 demonstrates strong dose dependent efficacy across MTAP deleted xenograft and PDX models of gastric and lung origin, where greater than 80% of tumor growth inhibition was detected, with no apparent toxicity. In addition, corresponding dose-dependent inhibition of SDMA is observed in the treated tumors. In an in vitro 28-day 3D human bone marrow model, AZ-PRMT5i-1 has reduced toxicity in erythroid and megakaryocyte cell lineages, compared to a first generation PRMT5 inhibitor. Conclusion: Overall, these studies demonstrate that AZ-PRMT5i-1 is a potent PRMT5 inhibitor demonstrating MTAP selectivity and anti-tumor activity in in vitro and in vivo pre-clinical models. Citation Format: James T. Lynch, Shaun Moore, Ivan Del Barco Barrantes, Lauren Bradshaw, Chris Chambers, Ted Hong, Sophie Cooke, Jelena Urosevic, Mercedes Vazquez-Chantada, James M. Smith, Anna Cronin, Benedicte Recolin, Sonja Gill, Susan Critchlow, Ho Man Chan, Emma Dean. AZ-PRMT5i-1: A potent MTAP-selective PRMT5 inhibitor with pharmacodynamic and monotherapy anti-tumor activity in MTAP-deleted tumours [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6272. |
