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

Author:

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

Abstract

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 (ΔT m = 8.83 ± 0.90°C) and isothermal titration calorimetry (K d = 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.

Funder

National Natural Science Foundation of China, Joint Fund of Research utilizing Large-scale Scientific Facilities

National Natural Science Foundation of China, Young Scientists Fund

Shaanxi Provincial Science and Technology Department

Education Department of Shaanxi Province, Scientific Research Plan Projects of Shaanxi Education Department

Shaanxi Administration of Traditional Chinese Medicine

Weiyang District Bureau of Science, Technology and Industry Information Technology

Xi'an Medical University

Publisher

International Union of Crystallography (IUCr)

Subject

Structural Biology

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