期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 6, 页码 3068-3087出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01960
关键词
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资金
- University of Michigan Developmental Research/GI SPORE Pilot Award [P50 CA130810]
- NIH [P30 CA046592]
- China Scholarship Council [201606240054]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Michigan Technology Tri-Corridor [085P1000817]
- Michigan Economic Development Corporation
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 IC50 = 0.6 mu M), 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 (IC50 = 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.
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