Structure-Based Discovery of (E)- and (Z)-4-Oxobut-2-enoate Derivatives as Novel Covalent Pin1 Inhibitors with
Meizhen Tian1, Yiran Chen2, Jie Zhou1
1Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Abstract:
Peptidyl-prolyl cis-trans isomerase Pin1 is a promising anticancer target that is overexpressed in numerous cancers and associated with poor prognosis. Herein, two series of covalent Pin1 inhibitors featuring an (E)- or a (Z)-4-oxobut-2-enoate moiety as the electrophilic warhead were discovered, and their binding features were revealed by six cocrystal structures. The binding kinetic investigations revealed that both (E)- and (Z)-4-oxobut-2-enoate warheads exhibited an appropriate electrophilic activity (kinact = 0.006-3.60 min-1), conferring them as favorable covalent warheads for developing potent Pin1 inhibitors. The SAR investigations resulted in four (Z)-isomers (T29, T39-T41: enzymatic IC50 = 0.02-0.08 μM) with excellent enzymatic activity, while the (E)-isomer T7 (enzymatic IC50 = 1.54 μM) was found to potently suppress the proliferation of MDA-MB-468 cancer cells by downregulating the Pin1 substrates c-Myc and Cyclin D1. Altogether, 4-oxobut-2-enoate derivatives were disclosed as new templates for further developing potent covalent Pin1 inhibitors.
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