Discovery of substituted indole derivatives as allosteric inhibitors ofm6A‐RNAmethyltransferase,METTL3‐14 complex

• DOI: 10.1002/ddr.21910
• Publication Date: 2022-01-18T13:25:28Z
• Authors: Je‐Heon Lee; Subin Kim; Mi Sun Jin; Yong‐Chul Kim
• Keywords: 0301 basic medicine; Leukemia, Myeloid, Acute; 03 medical and health sciences; Indoles; Humans; RNA; Methyltransferases; RNA, Messenger; Enzyme Inhibitors

m6A RNA methyltransferase (METTL3-14) catalyzes the methylation of adenosine in mRNA and plays important roles functions, it has been implicated progression multiple cancers, including acute myeloid leukemia (AML). In this study, we describe discovery first allosteric inhibitor METTL3-14 complex based on structure–activity relationship (SAR) optimization studies hit compound, 4-[2-[5-chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-yl]-ethoxy]benzoic acid (CDIBA). Compound 43n was optimized throughout modifications 4 different regions structure, displayed potent enzyme inhibitory activity (IC50 = 2.81 μM) an antiproliferative effect AML cell lines by suppressing level mRNA. The inhibition mechanism binding mode were interaction reversible noncompetitive profile at site along with selectivity for relative to each subunit or truncated enzyme.