Open AccessDiscovery of Bisubstrate Inhibitors for Protein N-Terminal Methyltransferase 1
Author(s) -
Dongxing Chen,
Guangping Dong,
Nicholas Noinaj,
Rong Huang
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b00206
Subject(s) - chemistry , methyltransferase , enzyme , cofactor , biochemistry , stereochemistry , dna , drug discovery , enzyme inhibitor , transferase , methylation
Protein N-terminal methyltransferase 1 (NTMT1) plays an important role in regulating mitosis and DNA repair. Here, we describe the discovery of a potent NTMT1 bisubstrate inhibitor 4 (IC 50 = 35 ± 2 nM) that exhibits greater than 100-fold selectivity against a panel of methyltransferases. We also report the first crystal structure of NTMT1 in complex with an inhibitor, which revealed that 4 occupies substrate and cofactor binding sites of NTMT1.