6LR9

HSP90 in complex with Debio0932

Summary for 6LR9

• Entry DOI: 10.2210/pdb6lr9/pdb
• Descriptor: Heat shock protein HSP 90-alpha, 2-[[6-(dimethylamino)-1,3-benzodioxol-5-yl]sulfanyl]-1-[2-(2,2-dimethylpropylamino)ethyl]imidazo[4,5-c]pyridin-4-amine, GLYCEROL, ... (4 entities in total)
• Functional Keywords: hsp90, debio0932, chaperone
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 28935.37

Authors

Cao, H.L. (deposition date: 2020-01-15, release date: 2021-01-13, Last modification date: 2023-11-29)

Primary citation

Qin, W.,Yu, F.,Zhou, H.,Li, P.,Zhou, F.,Li, H.J.,He, C.X.,Xing, L.,Zhou, X.,Zhao, D.,Li, P.Q.,Jin, X.,Wang, Q.S.,He, J.H.,Cao, H.L.
Complex crystal structure determination and anti-non-small-cell lung cancer activity of the Hsp90 N inhibitor Debio0932.
Acta Crystallogr D Struct Biol, 77:86-97, 2021

PubMed 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 (Hsp90). The absence of a crystal structure of the Hsp90-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 Hsp90-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 Hsp90, disabling its molecular-chaperone capability. The results of a thermal shift assay (ΔT = 8.83 ± 0.90°C) and isothermal titration calorimetry (K = 15.50 ± 1.30 nM) indicated strong binding and favourable thermodynamic changes in the binding of Hsp90 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 Hsp90, as determined by molecular-docking evaluation. Additionally, Debio0932 suppressed cell proliferation (IC 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.

PubMed: 33404528
DOI: 10.1107/S2059798320014990

Experimental method

X-RAY DIFFRACTION (2.196 Å)