45 (PB035) - Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP deleted cancers

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 methylothioadenosine (MTA) in cells. MTA in high concentrations is a selective inhibitor of PRMT5 type II methyltransferase. PRMT5 conjugated with WD-repeat containing proteins (MEP50/WDR77) forms methylosome, which regulates essential cellular functions via symmetric dimethylation (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. 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. Structurally enabled hit generation and optimization allowed quick expansion and delivery of several generations of compounds with novel IP, high target engagement in cells and selective potency in MTAP-deleted cell lines. Ryvu compounds selectively inhibit growth of MTAP-deleted cancer cells in prolonged 3D culture, which strongly correlates with inhibition of PRMT5-dependent protein symmetric dimethylation (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. Efficacy studies with our lead compound resulted in demonstration of tumor growth inhibition in MTAP -/- model, accompanied by significant inhibition of target proximal PD biomarker. Overall, these studies provide a rationale for the further optimization of our chemical series of MTA-cooperative PRMT5 inhibitors towards a clinical candidate. No conflict of interest.