2. Academic Validation
  3. Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1)

Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1)

  • J Med Chem. 2022 Feb 10;65(3):2174-2190. doi: 10.1021/acs.jmedchem.1c01686.
Liping Liu 1 2,  Rui Zhu 3,  Jiacheng Li 1 2,  Yuan Pei 2 4,  Shuangshuang Wang 3,  Pan Xu 1,  Mingyu Wang 1 2,  Yu Wen 3,  Hao Zhang 1,  Daohai Du 1,  Hong Ding 1,  Hualiang Jiang 1 2,  Kaixian Chen 1 2 5,  Bing Zhou 2 4,  Lifang Yu 3,  Cheng Luo 1 2 6 7
Affiliations

Affiliations

  • 1 Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
  • 4 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 5 Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
  • 7 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
PMID: 35089030 DOI: 10.1021/acs.jmedchem.1c01686
Abstract

The unique proline isomerase peptidyl-prolyl isomerase NIMA-interacting-1 (PIN1) is reported to activate numerous cancer-driving pathways simultaneously, and aberrant PIN1 activation is present in many human cancers. Here, we identified a novel hit compound, ZL-Pin01, that covalently modified PIN1 at Cys113 with an half-maximal inhibitory concentration (IC50) of 1.33 ± 0.07 μM through screening an in-house library. Crystallographic study drove the process of structure-guided optimization and led to the potent inhibitor ZL-Pin13 with an IC50 of 0.067 ± 0.03 μM. We obtained four co-crystal structures of PIN1 complexed with inhibitors that elucidated the detailed binding mode of the derivatives with PIN1. Interestingly, the co-crystal of PIN1 with ZL-Pin13 obtained by co-crystallization revealed the conformational change of Gln129 induced by the inhibitor. Furthermore, ZL-Pin13 effectively inhibited the proliferation and downregulated the PIN1 substrates in MDA-MB-231 cells. Collectively, we developed a potent covalent inhibitor of PIN1, ZL-Pin13, which could be an effective probe for studying the functional roles of PIN1.

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