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Anti-NSCLC activity in vitro of Hsp90N inhibitor KW-2478 and complex crystal structure determination of Hsp90N-KW-2478.
Li, Hui-Jin; Wang, Qi-Sheng; Han, Wen; Zhou, Huan; Li, Ping; Zhou, Fang; Qin, Wei; Zhao, Dong; Zhou, Xin; He, Chun-Xia; Xing, Lu; Li, Peng-Quan; Jin, Xi; Yu, Feng; He, Jian-Hua; Cao, Hui-Ling
2021
Source PublicationJournal of structural biology
Volume213Issue:2Pages:107710-107710
AbstractKW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90N (Hsp90N). Absence of complex crystal structure of Hsp90N-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90N-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59A; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, DeltaTm, 18.82±0.51°C) and isothermal titration calorimetry (ITC, Kd, 7.30±2.20nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90N. Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC50, 8.16muM for A549; 14.29muM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90N-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90N evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.
Document Type期刊论文
Identifierhttp://ir.sari.ac.cn/handle/39PL6PPA/3445
Collection中国科学院上海高等研究院
Recommended Citation
GB/T 7714
Li, Hui-Jin,Wang, Qi-Sheng,Han, Wen,et al. Anti-NSCLC activity in vitro of Hsp90N inhibitor KW-2478 and complex crystal structure determination of Hsp90N-KW-2478.[J]. Journal of structural biology,2021,213(2):107710-107710.
APA Li, Hui-Jin.,Wang, Qi-Sheng.,Han, Wen.,Zhou, Huan.,Li, Ping.,...&Cao, Hui-Ling.(2021).Anti-NSCLC activity in vitro of Hsp90N inhibitor KW-2478 and complex crystal structure determination of Hsp90N-KW-2478..Journal of structural biology,213(2),107710-107710.
MLA Li, Hui-Jin,et al."Anti-NSCLC activity in vitro of Hsp90N inhibitor KW-2478 and complex crystal structure determination of Hsp90N-KW-2478.".Journal of structural biology 213.2(2021):107710-107710.
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