Abstract 1140: A novel MTA non-competitive PRMT5 inhibitor

Abstract

The chromosome 9p21 (chr9p21) locus is deleted in almost 10% of all cancer types. This locus includes the CDKN2A gene that encodes the critical tumor suppressors p19-ARF and p16-INK4a. Methylthioadenosine phosphorylase (MTAP), a gene proximal to CDKN2A, is co-deleted in 80%-90% of tumors with CDKN2A deletion. MTAP plays a critical role in the methionine salvage pathway, and the deletion of MTAP results in the accumulation of its substrate methythioadenosine (MTA). Accumulation of MTA partially inhibits the activity of the arginine methyltransferase PRMT5, causing MTAP deficient cancer cells to be more sensitive to the genetic knockdown of PRMT5. In contrast to genetic knockdown, sensitivity to pharmacological inhibition of PRMT5 does not appear to stratify with MTAP status. However, currently known PRMT5 inhibitors all possess SAM competitive or uncompetitive MOIs, which generally require displacement of MTA from the active site for binding. We hypothesize that leveraging the high MTA state induced by MTAP deficiency will require an inhibitor that can bind PRMT5 without disrupting bound MTA. Here we report the discovery of a PRMT5 inhibitor with a novel binding mode that is compatible with MTA binding. While this compound possesses the desired MOI, it shows only modestly increased potency toward MTAP-null cells. Mathematical simulations of different inhibitor mechanisms indicate that the degree of selectivity that can be achieved depends on the difference in MTA levels between MTAP-null and WT cells. Our in vitro data suggest that the elevation in intracellular MTA concentrations that occurs with MTAP deletion is not sufficient to confer significantly increased sensitivity to PRMT5 inhibition. We anticipate that the therapeutic index that can be achieved between MTAP-null tumor cells and PRMT5-sensitive normal tissues will be similarly limited in vivo. Citation Format: Rohit Malik, Peter K. Park, Christopher M. Barbieri, Yuval Blat, Steven Sheriff, Carolyn A. Weigelt, Lisa M. Kopcho, Muge Celiktas, Max Ruzanov, Joseph G. Naglich, Jennifer L. Price, Mary Harner, Kevin M. Omalley, JIngjing Deng, William Schmitz, Guo Li, Zheming Ruan, Lan-ying Qin, Gerald J. Duke, Iyoncy Rodrigo, Mark R. Witmer, David G. Harden, Shilpa Demes, Brian J. Arey, Matt Soars, Brian E. Fink, Ashvinikumar V. Gavai, Gregory D. Vite, Charles F. Voliva. A novel MTA non-competitive PRMT5 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1140.

Discovery of a First-in-Class Inhibitor of the PRMT5–Substrate Adaptor Interaction

“…2-(4-Fluoro-5-methyl-6-oxopyridazin-1(6H)-yl)-N-(4-methyl-3-(N-(2-(pyridin-2-yl)ethyl)sulfamoyl)phenyl)acetamide (24). Compound 24 was prepared analogously to 23.…”

“…MTA-cooperative PRMT5 inhibitors are predicted to better leverage this synthetic lethality. Two such molecules have been recently disclosed with different degrees of selectivity for MTAPdeleted cancer cells in vitro 24 and in preclinical studies. 23 Inhibitors of the upstream enzyme MAT2A, which catalyzes the synthesis of SAM, have also been discovered and optimized to exploit the unbalanced SAM/MTA ratio of MTAP-deleted cancers.…”

Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers

“…Because of the critical role of PRMT5 as an essential gene in regulating hematopoiesis, the indiscriminate blockade of PRMT5 by non-MTA cooperative inhibitors has been associated with dose-limiting thrombocytopenia, anemia, and neutropenia. , Thus, the ability to selectively inhibit PRMT5 function in tumor cells while sparing nontumor cells is anticipated to exhibit an improved therapeutic index. Recently published patent applications from two other groups describe compounds that appear to target PRMT5•MTA, , Figure , and a recent poster described compound 1-(4-(methylsulfonyl)­benzyl)- N -(4-methylthiazol-2-yl)-1 H -indole-6-carboxamide as a novel MTA noncompetitive PRMT5 inhibitor …”

“…Recently published patent applications from two other groups describe compounds that appear to target PRMT5•MTA, 24,25 Figure 1, and a recent poster described compound 1-(4-(methylsulfonyl)benzyl)-N-(4-methylthiazol-2-yl)-1H-indole-6-carboxamide as a novel MTA noncompetitive PRMT5 inhibitor. 26 Herein, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in MTAP-del cells compared to MTAP-WT cells.…”

Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5

“…Accordingly, synthetic lethal inhibitors of the PRMT5 . MTA complex were discovered for the treatment of MTAP-deleted cancers, providing an option for therapeutic intervention. ,− …”