Abstract 2778: A novel MTA-cooperative PRMT5 inhibitor, MRTX1719, stabilizes the ternary MTA-PRMT5 complex and leads to synthetic lethality in MTAP deleted cancers

Abstract Previous studies have shown that cancer cell lines with homozygous deletion of the MTAP gene (MTAP del), are selectively sensitive to shRNA-mediated PRMT5 inhibition or MTA-cooperative PRMT5 inhibitors. PRMT5 is a methyltransferase that adds symmetric dimethyl arginine marks to various proteins essential for cell viability whereas MTAP is responsible for metabolizing MTA as part of the methionine salvage pathway. In MTAP del cells, MTA accumulates and partially inhibits PRMT5 activity by directly competing with SAM, the universal methyl donor and PRMT5 substrate. Thus, the deletion of MTAP leads to the formation of the PRMT5-MTA complex and functions as a synthetic lethal target. In this capacity, MTA-cooperative PRMT5 inhibitors are hypothesized to exhibit an increased therapeutic index compared to first generation PRMT5 inhibitors by preferentially inhibiting PRMT5 in MTAP del cancer cells while sparing normal cells. First generation PRMT5 inhibitors target either apo-PRMT5 or the PMRT5-SAM complex, while MRTX1719 preferentially binds the PRMT5-MTA complex, stabilizing the complex in an inactive state. Thermal shift analysis demonstrated rapid and complete binding of MRTX1719 to MTA-bound PRMT5 whereas binding to SAM-bound PRMT5 was delayed and incomplete after prolonged incubation. First generation clinical-stage PRMT5 inhibitors showed either preferential binding to the PRMT5-SAM complex or no selectivity between the PRMT5-MTA complex, the PMRT5-SAM complex, or apo-PRMT5 in the thermal shift assay, suggesting first generation inhibitors do not recapitulate the synthetic lethal phenotype in MTAP del cancers. In vitro, MRTX1719 exhibits a durable pharmacodynamic effect in MTAP del cells or MTAP WT cells incubated with MTA following drug washout in agreement with the long target residence time suggested by the thermal shift data. Moreover, in vivo time course studies confirm MRTX1719 exhibits potent and durable inhibition of PRMT5-dependent symmetric dimethyl arginine (SDMA) in MTAP del tumor xenografts. HemaTox™ viability assays were used to determine potency against human MTAP WT erythroid and myeloid cells where MRTX1719 was ~45-fold less potent compared to the MTAP del HCT116 cancer cell line. In contrast, first generation PRMT5 inhibitors were similarly potent against the HCT116 isogenic cell lines and human hematopoietic cells, irrespective of MTAP status. These data demonstrate MRTX1719 preferentially and potently binds PRMT5 in the presence of MTA and selectively inhibits MTAP del cancer cell lines. Moreover, the kinetic properties and selectivity profile suggest MRTX1719 will exhibit a significantly improved therapeutic window for the treatment of MTAP del cancer patients. Citation Format: Laura Vegar, Ruth Aranda, Laura Waters, Krystal Moya, Allan Hebbert, Christopher S. Smith, Jill Hallin, Briere M. David, Lars D. Engstrom, Darin Vanderpool, Matthew M. Marx, James G. Christensen, Peter A. Olson. A novel MTA-cooperative PRMT5 inhibitor, MRTX1719, stabilizes the ternary MTA-PRMT5 complex and leads to synthetic lethality in MTAP deleted cancers [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 2778.