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

• DOI: 10.1002/advs.202305593
• Publication Date: 2024-06-14T09:49:05Z
• Authors: Yan Peng; Yumeng Zhang; Ruan Fang; Hao Jiang; Gongcai Lan; Zhou Xu; Yajie Liu; Zhaoyang Nie; Lu Ren; Fengcan Wang; Shou‐De Zhang; Yuyong Ma; Peng Yang; Hong‐Hua Ge; Wei‐Dong Zhang; Cheng Luo; Ang Li; Weiwei He
• Keywords: Proteolysis; CDH1; Identification

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