A variety of covalent modifications of and structural changes to RNA have been identified and demonstrated to affect RNA processing, stability and translation. The enzymes that catalyze these changes, RNA modifying proteins or RMPs, represent a large class of novel targets for oncology and other disease indications that can be targeted with small molecule inhibitors. Methylation of adenosine at the N6 position (m6A) in mRNA is currently the most well-studied covalent RNA modification and is catalyzed by the RNA methyltransferase enzyme complex METTL3/METTL14. Once generated, m6A can modulate mRNA splicing, export, localization, degradation and translation and is implicated in AML and multiple solid tumor indications Although potent and selective inhibitors exist for several members of the Type I S-adenosylmethionine (SAM)-dependent methyltransferase family, no inhibitors have been published for METTL3/METTL14 to date. Accent Therapeutics has prioritized drug discovery efforts on METTL3/METTL14 and potent and selective inhibitors have been identified. Enzymatic assays using multiple methodologies have been developed to facilitate inhibitor identification and characterize mechanism of inhibition for compounds; select assays are capable of measuring compounds in the picomolar range of enzyme activity. Biophysical tools have been established to validate compound binding and measure inhibitor residence time. Cellular assays that measure m6A depletion in mRNA show good correlation with biochemical assay results. Anti-proliferative activity is seen for potent compounds.

Citation Format: P. Ann Boriack-Sjodin, Alexandra K. Gardino, Thomas A. Wynn, Shane M. Buker, Monique Laidlaw, E. Allen Sickmier, Brian L. Hodous, April W. Case, April E. Greene-Colozzi, Robert A. Copeland, Scott Ribich. Drug discovery efforts on the RNA protein methyltransferase METTL3/METTL14 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A112. doi:10.1158/1535-7163.TARG-19-A112