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

作者：Liu, Liping; Zhu, Rui; Li, Jiacheng; Pei, Yuan; Wang, Shuangshuang; Xu, Pan; Wang, Mingyu; Wen, Yu; Zhang, Hao; Du, Daohai; Ding, Hong; Jiang, Hualiang; Chen, Kaixian; Zhou, Bing; Yu, Lifang^*; Luo, Cheng^*

来源：Journal of Medicinal Chemistry, 2022, 65(3): 2174-2190.

DOI：10.1021/acs.jmedchem.1c01686

• STRUCTURE-BASED DESIGN
• BREAST-CANCER
• OVEREXPRESSION
• PROTEIN
• ISOMERIZATION
• AFFINITY

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 mu M 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 mu M. 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.

• 单位
  中国科学院; 中国科学院研究生院