Abstract P165: MRTX1719: A first-in-class MTA-cooperative PRMT5 inhibitor that selectively elicits antitumor activity in MTAP/CDKN2A deleted cancer models
Authors: Smith Christopher R. , Engstrom Lars D. , Kulyk Svitlana , Aranda Ruth , Waters Laura , Moya Krystal , Bowcut Victoria , Hebbert Allan , Trinh David , Briere David M. , Lawson J. David , Clarine Jeff , Rahbaek Lisa , Christensen James G. , Marx Matthew A. , Olson Peter 
Published: December 2021

Abstract
Nearly all oncology therapies target proteins that are hyperactivated in cancer; however, developing precision medicines for cancers that harbor a specific tumor suppressor gene loss remains one of the most significant challenges in cancer research. Previous studies demonstrated cancer cell lines harboring homozygous deletion of the MTAP gene (MTAP del) are selectively vulnerable to shRNA-mediated PRMT5 inhibition based on the concept of synthetic lethality. MTAP is adjacent to, and co-deleted with, the most commonly deleted tumor suppressor gene, CDKN2A. MTAP is deleted in ~10% of all cancers and is enriched in NSCLC, pancreatic cancer, mesothelioma, MPNST, and several other cancers. MTAP del cells accumulate the metabolite methylthioadenosine (MTA) which binds to, and partially inhibits, PRMT5 activity; however, current clinical-stage small molecule PRMT5 inhibitors have binding modes that are mutually exclusive with MTA binding and therefore are not selective for MTAP del cancers. To develop a potential precision medicine for MTAP del cancers, compounds that selectively bind to the PRMT5/MTA complex were discovered via a fragment-based approach using SPR complemented with structural insight utilizing X-ray crystallography. Optimization of the lead series identified MRTX1719, a potent inhibitor of PRMT5 activity (8 nM IC50) and cell viability (12 nM IC50) in HCT116 MTAP del cells with greater than 50-fold selectivity compared with HCT116 MTAP WT cells. MRTX1719 possesses favorable drug-like characteristics and human predicted oral PK properties. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine (SDMA) protein modification in MTAP del tumors that correlated with antitumor activity. In contrast, minimal inhibition of PRMT5-dependent SDMA and tumor growth inhibition was observed in MTAP WT tumor xenografts. Repeat dosing in mice also showed reduced effects in bone marrow compared to nonselective PRMT5 inhibitors currently in clinical trials, suggesting MRTX1719 may have an improved therapeutic index relative to these agents. MRTX1719 treatment resulted in dysregulated post-translational modification of key cancer and cell growth-related proteins, dysregulated RNA splicing, decreased proliferation and increased apoptosis in MTAP del cancer cells. Screens evaluating the effect of MRTX1719 on cell viability across panels of cancer cell lines and/or patient-derived xenograft tumor models demonstrated broad anti-tumor activity across MTAP-deleted tumor models. Select targeted therapy and chemotherapy combinations augmented the activity of MRTX1719 and in some models converged on phospho-Rb inhibition to block tumor growth. Together, these data demonstrate that MRTX1719, a selective PRMT5/MTA inhibitor, represents a promising therapeutic strategy for patients with MTAP del cancers.
Citation Format: Christopher R. Smith, Lars D. Engstrom, Svitlana Kulyk, Ruth Aranda, Laura Waters, Krystal Moya, Victoria Bowcut, Allan Hebbert, David Trinh, David M. Briere, J. David Lawson, Jeff Clarine, Lisa Rahbaek, James G. Christensen, Matthew A. Marx, Peter Olson. MRTX1719: A first-in-class MTA-cooperative PRMT5 inhibitor that selectively elicits antitumor activity in MTAP/CDKN2A deleted cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P165.