Complex Crystal Structure Determination and in vitro Anti–non–small Cell Lung Cancer Activity of Hsp90N Inhibitor SNX-2112

• DOI: 10.3389/fcell.2021.650106
• Publication Date: 2021-03-29T05:44:57Z
• Authors: Dong Zhao; Yi-Ming Xu; Lu-Qi Cao; Feng Yu; Huan Zhou; Wei Qin; Hui-Jin Li; Chun-Xia He; Lu Xing; Xin Zhou; Peng-Quan Li; Xin Jin; Yuan He; Jian-Hua He; Hui-Ling Cao
• Keywords: Isothermal Titration Calorimetry; Docking (animal); Hsp90 inhibitor; Geldanamycin

SNX-2112, as a promising anticancer lead compound targeting heat shock protein 90 (Hsp90), absence of complex crystal structure Hsp90 N -SNX-2112 hindered further structural optimization and understanding on molecular interaction mechanism. Herein, high-resolution was successfully determined by X-ray diffraction, resolution limit, 2.14 Å, PDB ID 6LTK, their analyzed in detail, which suggested that SNX-2112 well accommodated the ATP-binding pocket to disable chaperone activity Hsp90, therefore exhibiting favorable inhibiting three non–small cell lung cancer (NSCLC) lines (IC 50 , 0.50 ± 0.01 μM for A549, 1.14 1.11 H1299, 2.36 0.82 H1975) inhibited proliferation, induced cycle arrest, aggravated apoptosis. exhibited high affinity beneficial thermodynamic changes during binding process with its target confirmed thermal shift assay (TSA, ΔTm, −9.51 1.00°C) isothermal titration calorimetry ( K d 14.10 1.60 nM). Based analysis, 32 novel derivatives were designed, 25 new ones displayed increased force verified docking evaluation. The results would provide references guides anti-NSCLC drug development based SNX-2112.