Abstract 1806: Discovery of novel MTA-cooperative PRMT5 inhibitors as a targeted therapeutics for MTAP deleted cancers

Abstract

Abstract Targeting PRMT5 in MTAP-deleted tumors in a synthetic lethal approach represents a promising antitumor strategy across many tumor types. Metabolic gene MTAP is localized at the 9p21 chromosome in the close proximity to CDKN2A tumor-suppressor locus. Co-deletion of MTAP may be observed in 80-90% of all tumors harboring homozygous deletion of CDKN2A, which represents 10-15% of all human tumors. MTAP deletion results in a massive accumulation of methylotioadenosine (MTA) in cells. MTA in high concentrations is a selective inhibitor of PRMT5 type II methyltransferase. PRMT5 conjugated with WD-repeat containing protein (WDR77) builds methylosome, which regulates essential cellular functions via symmetric demethylation (SDMA) of target proteins involved in regulation of gene expression, RNA splicing, signal transduction, metabolism and other functions. Accumulation of MTA in cells with MTAP deletion causes a partial inhibition of the methylation activity of PRMT5, which in turn reduces the level of symmetric arginine dimethylation of the whole proteome, and thus an increased sensitivity of cells to modulation of the methylosome activity. Therapeutic targeting of PRMT5 in homozygous MTAP-deleted cancers constitute a promising strategy of selective killing of genetically defined cancer cells. Currently available clinical stage PRMT5 small molecule inhibitors are not MTA-cooperative and therefore are not selective in tumors harboring MTAP deletion. Here we present MTA-cooperative PRMT5 inhibitors, which selectively inhibit the growth of MTAP deleted cancer cells. Ryvu has identified a series of MTA-cooperative PRMT5 inhibitors which have good drug-like physicochemical properties and block methyltransferase activity with nanomolar IC50 values. Ryvu compounds selectively inhibit growth of MTAP deleted cancer cells in prolonged 3D culture, which strongly correlates with inhibition of PRMT5-dependent protein symmetric demethylation (SDMA) in those cells. Selectivity between effects observed in MTAP deleted and WT cells exceeds 100-fold both for SDMA and growth inhibition. The DMPK profile of these compounds allows for oral administration, which enables testing dose-dependent antitumor activity in MTAP null tumor xenograft-bearing mice. Overall, these studies provide rationale for further optimization of chemical series towards clinical candidate. Citation Format: Oleksandr Levenets, Anna Bartosik, Marta Sowińska, Karol Zuchowicz, Sujit Sasmal, Klara Korta-Piątek, Adam Radzimierski, Paulina Niedziejko, Oleksandr Popika, Mateusz Świrski, Agata Stachowicz, Maciej Mikulski, Magdalena Sieprawska-Lupa, Katarzyna Banaszak, Kinga Michalik, Kamil Kuś, Monika Madej, Adrian Podkowa, Karolina Gluza, Grzegorz Satała, Ewelina Cieluch, Dobrosława Krzemień, Andrzej Gondela, Grzegorz Ćwiertnia, Marek Wronowski, Nicolas Boutard, Aleksandra Więckowska, Joanna Zezula, Justyna Jabłońska, Mirosława Gładysz, Igor Tomczyk, Jacek Faber, Marcin Serocki, Eliza Drwal, Kamila Kozłowska-Tomczyk, Marta Skoda, Martin Swarbrick, Krzysztof Brzózka, Mateusz Nowak. Discovery of novel MTA-cooperative PRMT5 inhibitors as a targeted therapeutics for MTAP deleted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1806.