Structure-Based Discovery of (E)- and (Z)-4-Oxobut-2-enoate Derivatives as Novel Covalent Pin1 Inhibitors with Antitumor Activity

  • J Med Chem. 2026 Jul 23;69(14):16529-16549. doi: 10.1021/acs.jmedchem.6c00041.
Meizhen Tian  1 ,  Yiran Chen  2 ,  Jie Zhou  1 ,  Guonan Cui  1 ,  Xiaoyu Wang  1 ,  Jing Jin  2 ,  Bailing Xu  1
Affiliations
  • 1. Beijing 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.
  • 2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 42388100 DOI: 10.1021/acs.jmedchem.6c00041
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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