We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Discovery of substituted indole derivatives as allosteric inhibitors of m<sup>6</sup>A‐RNA methyltransferase, METTL3‐14 complex.
- Authors
Lee, Je‐Heon; Kim, Subin; Jin, Mi Sun; Kim, Yong‐Chul
- Abstract
m6A RNA methyltransferase (METTL3‐14) catalyzes the methylation of adenosine in mRNA and plays important roles in mRNA functions, and it has been implicated in the progression of multiple cancers, including acute myeloid leukemia (AML). In this study, we describe the discovery of the first allosteric inhibitor of the METTL3‐14 complex based on structure–activity relationship (SAR) and optimization studies of the hit compound, 4‐[2‐[5‐chloro‐1‐(diphenylmethyl)‐2‐methyl‐1H‐indol‐3‐yl]‐ethoxy]benzoic acid (CDIBA). Compound 43n was optimized throughout the modifications of 4 different regions of the structure, and it displayed potent enzyme inhibitory activity of the METTL3‐14 complex (IC50 = 2.81 μM) and an antiproliferative effect in the AML cell lines by suppressing the m6A level of mRNA. The inhibition mechanism and binding mode of 43n were based on the interaction of the reversible and noncompetitive inhibitory profile at the allosteric site along with selectivity for the METTL3‐14 complex relative to each subunit enzyme or truncated complex enzyme.
- Subjects
INDOLE derivatives; ADENOSINES; ACUTE myeloid leukemia; METHYLTRANSFERASES; MULTIENZYME complexes; BENZOIC acid
- Publication
Drug Development Research, 2022, Vol 83, Issue 3, p783
- ISSN
0272-4391
- Publication type
Article
- DOI
10.1002/ddr.21910