Open AccessStructure-Based Design of N-(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S-Transferase Omega 1 Inhibitors
Author(s) -
Weiyang Dai,
Soma Samanta,
Ding Xue,
E.M. Petrunak,
Jeanne A. Stuckey,
Yanyan Han,
Duxin Sun,
Yong Wu,
Nouri Neamati
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.8b01960
Subject(s) - chemistry , thiazole , moiety , cocrystal , stereochemistry , structure–activity relationship , amide , glutathione , ic50 , combinatorial chemistry , lead compound , enzyme , biochemistry , molecule , hydrogen bond , in vitro , organic chemistry
Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC 50 = 0.6 μM), compound 18 was synthesized and cocrystallized with GSTO1. Modification on the amide moiety of hit compound 10 significantly increased the GSTO1-1 inhibitory potency. We solved the cocrystal structures of new derivatives, 37 and 44, bearing an amide side chain bound to GSTO1. These new structures showed a reorientation of the phenyl thiazole core of inhibitors, 37 and 44, when compared to 18. Guided by the cocrystal structure of GSTO1:44, analogue 49 was designed, resulting in the most potent GSTO1-1 inhibitor (IC 50 = 0.22 ± 0.02 nM) known to date. We believe that our data will form the basis for future studies of developing GSTO1-1 as a new drug target for cancer therapy.