Abstract 6254: The discovery and preclinical characterization of the SAM-competitive PRMT5 inhibitor UCT-000445

Abstract

Abstract Protein arginine methyltransferase 5 (PRMT5) is a methyltransferase enzyme that symmetrically dimethylates arginine residues of histones, transcription elongation factors, translation regulators, and transcription factors like p53. It also regulates the activity of MAPK and PI3K signaling through methylation and activation of various receptor tyrosine kinases. As such, it has epigenetic effects that may be therapeutic in oncology. Successful clinical development of PRMT5 inhibitors will depend on upon utilizing this unique inhibitor modality and identifying those cancers with sensitivity to PRMT5 inhibition. By evaluating the potency and efficacy of several SAM-competitive, substrate-competitive, and MTA-cooperative PRMT5 inhibitors using a large (n>500), diverse panel of human cancer cell lines, we determined that the SAM-competitive inhibitor modality offers the best therapeutic potential thanks to its larger therapeutic window in vitro. This screening approach also identified several solid tumor histologies that were extremely sensitive to PRMT5 inhibition. Using our proprietary chemistry and by screening through the panel of human cancer cell lines, we identified UCT-000445, a SAM-competitive PRMT5 inhibitor with high selectivity over PRMT9 and good pharmacokinetic properties. Moreover, efficacy UCT-000445 is achieved regardless of MTAP gene status in histologies outside of hematological malignancies and including colon. UCT-000445 potently inhibits tumor growth in multiple human xenograft models of cancers, including but not limited to colon and lung cancers. The responses observed are durable upon cessation of treatment. Marked combined efficacy was also observed with standard of care treatment in these cancer types. UCT-000445 was well tolerated in vivo and using a CD-1 nude mouse model we found that while reticulocyte proliferation (a surrogate marker for bone marrow cytopenias) is abrogated by continuous treatment with UCT-000445, the use of intermittent dosing schedules overcomes this effect, while yielding equivalent efficacy. Our data with UCT-000445 indicate that SAM-competitive PRMT5 inhibitors may represent a novel and compelling therapeutic strategy for the treatment of multiple solid tumors. Citation Format: Martina S. McDermott, Neil A. O'Brien, Brendan O'Boyle, Michael Bartberger, Oliver C. Losón, Kevin Chau, Ella Schwab, Jenny Hong, Jiaying Zhou, Chuhong Hu, Tong Luo, Raul Ayala, John Glasby, Brian M. Stoltz, Dennis J. Slamon. The discovery and preclinical characterization of the SAM-competitive PRMT5 inhibitor UCT-000445 [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 6254.