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Journal of structural biology

Journal of structural biology

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Anti-NSCLC activity in vitro of Hsp90N inhibitor KW-2478 and complex crystal structure determination of Hsp90N-KW-2478

Published:1 June 2021 DOI: 10.1016/j.jsb.2021.107710
Hui-Jin Li , Qi-Sheng Wang , Wen Han , Huan Zhou , Ping Li , Fang Zhou , Wei Qin , Dong Zhao , Xin Zhou , Chun-Xia He , Lu Xing , Peng-Quan Li , Xi Jin , Feng Yu , Jian-Hua He , Hui-Ling Cao

Abstract

KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90?N (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: 1.59??; 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, ΔTm, 18.82?±?0.51?°C) and isothermal titration calorimetry (ITC, Kd, 7.30?±?2.20?nM) 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, 8.16?μM for A549; 14.29?μM 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.

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Materials Related products
Procduct Name CAS Molecular Formula Supplier Price
KW-2478 819812-04-9 C30H42N2O9 113 suppliers $44.00-$4171.86
KW-2478 819812-04-9 C30H42N2O9 113 suppliers $44.00-$4171.86
KW-2478 819812-04-9 C30H42N2O9 113 suppliers $44.00-$4171.86
KW-2478 819812-04-9 C30H42N2O9 113 suppliers $44.00-$4171.86

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