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

文献类型：期刊论文

作者Liu, Liping4,5; Zhu, Rui3; Li, Jiacheng4,5; Pei, Yuan2,4; Wang, Shuangshuang3; Xu, Pan5; Wang, Mingyu4,5; Wen, Yu3; Zhang, Hao5; Du, Daohai5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-02-10
卷号65期号:3页码:2174-2190
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c01686
通讯作者Yu, Lifang(cluo@simm.ac.cn) ; Luo, Cheng(lfyu@sat.ecnu.edu.cn)
英文摘要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.
WOS关键词STRUCTURE-BASED DESIGN ; BREAST-CANCER ; OVEREXPRESSION ; PROTEIN ; ISOMERIZATION ; AFFINITY
资助项目Shanghai National Protein Science Center (Shanghai Science Research Center Protein Expression and Purification System) ; National Key R&D Program of China[2021ZD0203900] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[21820102008] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000797933300033
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/301410]  
专题新药研究国家重点实验室
通讯作者Yu, Lifang; Luo, Cheng
作者单位1.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, Qingdao 266237, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai 201203, Peoples R China
3.East China Normal Univ, Sch Chem & Mol Engn, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Shanghai 200062, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Drug Discovery & Design Ctr, Ctr Chem Biol, State Key Lab Drug Res,Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Liping,Zhu, Rui,Li, Jiacheng,et al. Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1)[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(3):2174-2190.
APA Liu, Liping.,Zhu, Rui.,Li, Jiacheng.,Pei, Yuan.,Wang, Shuangshuang.,...&Luo, Cheng.(2022).Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1).JOURNAL OF MEDICINAL CHEMISTRY,65(3),2174-2190.
MLA Liu, Liping,et al."Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1)".JOURNAL OF MEDICINAL CHEMISTRY 65.3(2022):2174-2190.

入库方式： OAI收割

来源：上海药物研究所

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