Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1-Mediated Proteolysis of CENP-A.
Yan PengYumeng ZhangRuan FangHao JiangGongcai LanZhou XuYajie LiuZhaoyang NieLu RenFengcan WangShou-De ZhangYuyong MaPeng YangHong-Hua GeWei-Dong ZhangCheng LuoAng LiWeiwei HePublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2024)
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.
Keyphrases
- small molecule
- cell cycle
- cell proliferation
- protein protein
- cancer therapy
- high resolution
- molecular docking
- structure activity relationship
- high throughput
- gene expression
- risk assessment
- immune response
- adverse drug
- magnetic resonance
- drug delivery
- binding protein
- inflammatory response
- copy number
- combination therapy
- electronic health record
- single cell
- genome wide