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
  • 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.

Products