Complex crystal structure determination and anti‐non‐small‐cell lung cancer activity of the Hsp90N inhibitor Debio0932

Debio0932 is a promising lead compound in phase I clinical trials targeting the N‐terminal ATP‐binding pocket of the molecular chaperone heat‐shock protein 90 (Hsp90N). The absence of a crystal structure of the Hsp90N–Debio0932 complex, however, has impeded further structural optimization of Debio09...

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Published in:Acta crystallographica. Section D, Biological crystallography. Biological crystallography., 2021-01, Vol.77 (1), p.86-97
Main Authors: Qin, Wei, Yu, Feng, Zhou, Huan, Li, Ping, Zhou, Fang, Li, Hui-Jin, He, Chun-Xia, Xing, Lu, Zhou, Xin, Zhao, Dong, Li, Peng-Quan, Jin, Xi, Wang, Qi-Sheng, He, Jian-Hua, Cao, Hui-Ling
Format: Article
Language:English
Subjects:
anti‐NSCLC drug development
Apoptosis
Binding
Calorimetry
Cell proliferation
Clinical trials
complex crystal structure
Crystal structure
Debio0932
Derivatives
Drug development
Hsp90
Lead compounds
Lung cancer
molecular interactions
Molecular structure
Non-small cell lung carcinoma
Optimization
Titration
Titration calorimetry
Tumor cell lines
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Summary:Debio0932 is a promising lead compound in phase I clinical trials targeting the N‐terminal ATP‐binding pocket of the molecular chaperone heat‐shock protein 90 (Hsp90N). The absence of a crystal structure of the Hsp90N–Debio0932 complex, however, has impeded further structural optimization of Debio0932 and understanding of the molecular‐interaction mechanism. Here, a high‐resolution crystal structure of the Hsp90N–Debio0932 complex was successfully determined (resolution limit 2.20 Å; PDB entry 6lr9) by X‐ray diffraction and the molecular‐interaction mechanism was analysed in detail, which suggested that Debio0932 suppresses cancer cells by accommodating itself in the ATP‐binding pocket of Hsp90N, disabling its molecular‐chaperone capability. The results of a thermal shift assay (ΔTm = 8.83 ± 0.90°C) and isothermal titration calorimetry (Kd = 15.50 ± 1.30 nM) indicated strong binding and favourable thermodynamic changes in the binding of Hsp90N and Debio0932. Based on the crystal structure of the complex and on molecular‐interaction analysis, 30 new Debio0932 derivatives were designed and nine new derivatives exhibited increased binding to Hsp90N, as determined by molecular‐docking evaluation. Additionally, Debio0932 suppressed cell proliferation (IC50 values of 3.26 ± 2.82 µM for A549, 20.33 ± 5.39 µM for H1299 and 3.16 ± 1.04 µM for H1975), induced cell‐cycle arrest and promoted apoptosis in three non‐small‐cell lung cancer (NSCLC) cell lines. These results provide novel perspectives and guidance for the development of new anti‐NSCLC drugs based on the lead compound Debio0932. A high‐resolution crystal structure of the Hsp90N–Debio0932 complex was successfully determined. Based on the crystal structure of the complex and on molecular‐interaction analysis using thermal shift analysis and isothermal titration calorimetry, 30 new Debio0932 derivatives were designed and evaluated by molecular docking. Moreover, Debio0932 exhibited favourable in vitro anti‐non‐small‐cell lung cancer activity.
ISSN:2059-7983
0907-4449
2059-7983
1399-0047
DOI:10.1107/S2059798320014990