Structure-Based Design of N -(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S-Transferase Omega 1 Inhibitors

Dai, Weiyang; Samanta, Soma; Xue, Ding; Petrunak, Elyse M.; Stuckey, Jeanne A.; Han, Yanyan; Sun, Duxin; Wu, Yong; Neamati, Nouri

doi:10.1021/acs.jmedchem.8b01960

Structure-Based Design of N -(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S-Transferase Omega 1 Inhibitors

Journal Article · Fri Feb 08 00:00:00 EST 2019 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b01960· OSTI ID:1504972

^[1]; Samanta, Soma ^[2]; Xue, Ding ^[2]; Petrunak, Elyse M. ^[2]; Stuckey, Jeanne A. ^[2]; Han, Yanyan ^[2]; Sun, Duxin ^[2]; ^[3]; ^[2]

Univ. of Michigan, Ann Arbor, MI (United States); Sichuan Univ., Chengdu (People's Republic of China)
Univ. of Michigan, Ann Arbor, MI (United States)
Sichuan Univ., Chengdu (People's Republic of China)

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 $$μ$$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. Furthermore, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: China Scholarship Council (CSC); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1504972

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 6 Vol. 62; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Structure-Based Design of N -(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S-Transferase Omega 1 Inhibitors

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