Abstract C135: Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers

Abstract

Abstract Homozygous deletions of the p16/CDKN2a (cyclin dependent kinase inhibitor 2A) locus, which is responsible for regulating the cell cycle, are commonly found in cancer and often involve the deletion of adjacent genes. One such adjacent gene is methylthioadenosine phosphorylase (MTAP), involved in metabolism, located on chromosome 9p21 in close proximity to the p16/CDKN2A tumor-suppressor locus. Co-deletion of MTAP is observed in approximately 80-90% of tumors with homozygous deletion of CDKN2A, representing 10-15% of all human tumors. These tumor types, including non-small cell lung cancer, pancreatic adenocarcinoma, glioblastoma, and mesothelioma, have a poor prognosis, highlighting the significant unmet medical need in this area. Deletion of MTAP leads to a significant accumulation of methylthioadenosine (MTA) in cells. MTA, at high concentrations, selectively inhibits the PRMT5 methyltransferase enzyme, competing with the substrate S-adenosylmethionine (SAM) required for methylation reactions. As a result, the overall level of symmetric arginine dimethylation throughout the proteome is reduced. This heightened sensitivity to modulation of methylosome activity makes cells with MTAP deletion more susceptible to therapeutic targeting of PRMT5. Hence, selective targeting of PRMT5 in cancers with homozygous MTAP deletion represents a promising strategy for specifically eliminating cancer cells with this genetic alteration. Ryvu is developing two independent series of PRMT5 inhibitors characterized by good drug-like physicochemical properties and inhibition of methyltransferase activity with IC50 values in the low nanomolar range. Structure-based lead optimization enabled rapid expansion and delivery of a compound library with novel intellectual property (IP), high target engagement in cells and selective potency in MTAP-deleted cell lines. In long-term three-dimensional (3D) cell culture, Ryvu compounds selectively inhibit the growth of MTAP-deficient cancer cells, which correlate strongly with the inhibition of PRMT5-dependent symmetric protein dimethylation  (SDMA) in these cells. The synthesized library allowed the identification of compounds with more than 350-fold selectivity between the effects observed in MTAP-deficient and WT cells for both SDMA and growth inhibition. The DMPK profile of these compounds allows for oral administration, which enables testing of antitumor activity in MTAP null tumor xenograft bearing mice. The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Taken together, these studies provide a rationale for the further development of our chemical series of MTA cooperative PRMT5 inhibitors toward a clinical candidate. Citation Format: Adam Radzimierski, Aneta Bobowska, Agata Stachowicz, Kamil Kus, Kamila Kozłowska-Tomczyk, Agnieszka Ludwig-Słomczyńska, Aniela Gołas, Paulina Podkalicka, Andrzej Gondela, Nicolas Boutard, Grzegorz Ćwiertnia, Krzysztof Brzózka, Anna Bartosik, Mateusz Nowak, Didier Pez. Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C135.