Open AccessStructure-based Discovery of Cell-Potent Peptidomimetic Inhibitors for Protein N-Terminal Methyltransferase 1
Author(s) -
Dongxing Chen,
Guangping Dong,
Youchao Deng,
Nicholas Noinaj,
Rong Huang
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00012
Subject(s) - methyltransferase , methylation , peptidomimetic , ic50 , chemistry , cell , regulator , biochemistry , cell growth , enzyme , stereochemistry , in vitro , gene , peptide
Protein N-terminal methyltransferases (NTMTs) catalyze the methylation of the α-N-terminal amines of proteins starting with an X-P-K/R motif. NTMT1 has been implicated in various cancers and in aging, implying its role as a potential therapeutic target. Through structural modifications of a lead NTMT1 inhibitor, BM30 , we designed and synthesized a diverse set of inhibitors to probe the NTMT1 active site. The incorporation of a naphthyl group at the N-terminal region and an ortho -aminobenzoic amide at the C-terminal region of BM30 generates the top cell-potent inhibitor DC541 , demonstrating increased activity on both purified NTMT1 (IC 50 of 0.34 ± 0.02 μM) and the cellular α-N-terminal methylation level of regulator of chromosome condensation 1 (RCC1, IC 50 value of 30 μM) in human colorectal cancer HT29 cells. Furthermore, DC541 exhibits over 300-fold selectivity to several methyltransferases. This study points out the direction for the development of more cell-potent inhibitors for NTMT1.