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

被引：1

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

来源：

ADVANCED SCIENCE | 2024年 / 11卷 / 29期

基金：

中国国家自然科学基金;

关键词：

Cdh1; CENP-A regulation; colchicine-binding site inhibitor; indole terpenoid; target identification; CELL-CYCLE; TUBULIN; PHOSPHORYLATION; UBIQUITYLATION; DEPOSITION; COLCHICINE; PROTEIN; DESIGN; MARKER;

D O I：

10.1002/advs.202305593

中图分类号：

O6 [化学];

学科分类号：

0703 ;

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

引用

页数：14