Discovery of Novel Pyrimidine Derivatives as Human Pin1 Covalent Inhibitors

  • ACS Med Chem Lett. 2024 Dec 20;16(1):101-108. doi: 10.1021/acsmedchemlett.4c00477.
Meizhen Tian  1 ,  Xiaoyu Wang  1 ,  Guodong Tang  2 ,  Guonan Cui  1 ,  Jie Zhou  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: 39811131 DOI: 10.1021/acsmedchemlett.4c00477
Abstract

PIN1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) is a unique peptidyl-prolyl isomerase (PPIase), and inactivation of PIN1 with a covalent inhibitor is a potential strategy for developing Anticancer agents. Herein, a series of sulfolane amino-substituted 2-chloro-5-nitropyrimidine derivatives were disclosed as structurally distinct covalent inhibitors toward PIN1, which were validated for their covalent binding to Cys113 of PIN1 by X-ray cocrystal structures of compounds 4a (IC50 = 11.55 μM) and 6a (IC50 = 3.15 μM). This work provided a new approach for covalent inhibition of PIN1 by taking advantage of the 2-chloro-5-nitropyrimidine as the electrophilic warhead, which might benefit the discovery of potent and drug-like PIN1 inhibitors.

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