Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1‐Mediated Proteolysis of CENP‐A
Source abstract
Abstract
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. 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 β‐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.
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Research context
OpenAlex topics: Plant biochemistry and biosynthesis · Plant Reproductive Biology · Phytochemical compounds biological activities
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Shanghai Key Laboratory of New Drug Design School of Pharmacy East China University of Science and Technology Shanghai 200237 China
State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai 200032 China
Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
Henan Institute of Advanced Technology and College of Chemistry Zhengzhou University Zhengzhou 450001 China
State Key Laboratory of Plateau Ecology and Agriculture Qinghai University Xining 810016 China
Institute of Physical Science and Information Technology Anhui University Hefei 230601 China
Department of Phytochemistry School of Pharmacy Second Military Medical University Shanghai 200433 China
Funding
National Natural Science Foundation of China · Chinese Academy of Sciences · Science and Technology Commission of Shanghai Municipality
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