文献类型：期刊文献

英文题名：Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1-Mediated Proteolysis of CENP-A

作者：Peng, Yan[1];Zhang, Yumeng[1];Fang, Ruan[1,2];Jiang, Hao[3];Lan, Gongcai[1];Xu, Zhou[2];Liu, Yajie[1];Nie, Zhaoyang[2,4,5];Ren, Lu[2];Wang, Fengcan[1];Zhang, Shou-De[6];Ma, Yuyong[2];Yang, Peng[2,4,5];Ge, Hong-Hua[7];Zhang, Wei-Dong[1,8];Luo, Cheng[3];Li, Ang[2,4,5];He, Weiwei[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Chem Biol, Shanghai 200032, Peoples R China;[3]Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China;[4]Zhengzhou Univ, Henan Inst Adv Technol, Zhengzhou 450001, Peoples R China;[5]Zhengzhou Univ, Coll Chem, Zhengzhou 450001, Peoples R China;[6]Qinghai Univ, State Key Lab Plateau Ecol & Agr, Xining 810016, Peoples R China;[7]Anhui Univ, Inst Phys Sci & Informat Technol, Hefei 230601, Peoples R China;[8]Second Mil Med Univ, Sch Pharm, Dept Phytochem, Shanghai 200433, Peoples R China

年份：2024

卷号：11

期号：29

外文期刊名：ADVANCED SCIENCE

收录：;EI(收录号：20242416260304);WOS:【SCI-EXPANDED(收录号:WOS:001247125700001)】；

基金：This paper is dedicated to the memory of Prof. Hualiang Jiang. The authors thank Profs. Yang Wang, Kuiling Ding, Xin Zhang, Linghua Meng, and Mr. Fahui Zhu for helpful discussions and Institutes of Biomedical Science (IBS) at Fudan University and Shanghai Synchrotron Radiation Facility (SSRF) for technical assistance. This work was supported by National Natural Science Foundation of China (21931014, U2002221, 21572064, and 81502956), Chinese Academy of Sciences (YSBR-095, XBZG-ZDSYS-202303, 121731KYSB20190039, and QYZDB-SSW-SLH040), and Science and Technology Commission of Shanghai Municipality (JCYJ-SHFY-2022-005 and 20430713400). A.L. is grateful to the New Cornerstone Science Foundation for the XplorerPrize. The original results described in this paper were uploaded to the preprint server for biology, bioRxiv (), on April 26, 2023.

语种：英文

外文关键词：Cdh1; CENP-A regulation; colchicine-binding site inhibitor; indole terpenoid; target identification

摘要：Centromere protein A (CENP-A), a histone H3 variant specific to centromeres, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. A structure-activity relationship (SAR) study of the cell-cycle-arresting indole terpenoid mimic JP18 leads to the discovery of two more potent analogs, (+)-6-Br-JP18 and (+)-6-Cl-JP18. Tubulin is identified as a potential cellular target of these halogenated analogs by using the drug affinity responsive target stability (DARTS) based method. X-ray crystallography analysis reveals that both molecules bind to the colchicine-binding site of beta-tubulin. Treatment of human cells with microtubule-targeting agents (MTAs), including these two compounds, results in CENP-A accumulation by destabilizing Cdh1, a co-activator of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. This study establishes a link between microtubule dynamics and CENP-A accumulation using small-molecule tools and highlights the role of Cdh1 in CENP-A proteolysis. The indole terpenoid mimic (+)-6-Br-JP18 disrupts spindle microtubule assembly by targeting the colchicine-binding site of beta-tubulin, which leads to downregulation of Cdh1, a co-activator of the APC/C E3 ubiquitin ligase, and accumulation of its substrate CENP-A in human cells. image