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Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1-Mediated Proteolysis of CENP-A.
Peng, Yan; Zhang, Yumeng; Fang, Ruan; Jiang, Hao; Lan, Gongcai; Xu, Zhou; Liu, Yajie; Nie, Zhaoyang; Ren, Lu; Wang, Fengcan; Zhang, Shou-De; Ma, Yuyong; Yang, Peng; Ge, Hong-Hua; Zhang, Wei-Dong; Luo, Cheng; Li, Ang; He, Weiwei.
Affiliation
  • Peng Y; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • Zhang Y; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • Fang R; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • Jiang H; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
  • Lan G; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Xu Z; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • Liu Y; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
  • Nie Z; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • Ren L; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
  • Wang F; Henan Institute of Advanced Technology and College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China.
  • Zhang SD; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
  • Ma Y; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • Yang P; State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, 810016, China.
  • Ge HH; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
  • Zhang WD; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
  • Luo C; Henan Institute of Advanced Technology and College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China.
  • Li A; Institute of Physical Science and Information Technology, Anhui University, Hefei, 230601, China.
  • He W; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Adv Sci (Weinh) ; : e2305593, 2024 Jun 14.
Article in En | MEDLINE | ID: mdl-38873820
ABSTRACT
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 ß-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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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Adv Sci (Weinh) Year: 2024 Document type: Article
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Adv Sci (Weinh) Year: 2024 Document type: Article