Zhao Dong, Xu Yi-Ming, Cao Lu-Qi, Yu Feng, Zhou Huan, Qin Wei, Li Hui-Jin, He Chun-Xia, Xing Lu, Zhou Xin, Li Peng-Quan, Jin Xin, He Yuan, He Jian-Hua, Cao Hui-Ling
Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic & Translational Medicine, Xi'an Medical University, Xi'an, China.
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, United States.
Front Cell Dev Biol. 2021 Mar 29;9:650106. doi: 10.3389/fcell.2021.650106. eCollection 2021.
SNX-2112, as a promising anticancer lead compound targeting heat shock protein 90 (Hsp90), absence of complex crystal structure of Hsp90 -SNX-2112 hindered further structural optimization and understanding on molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90 -SNX-2112 was successfully determined by X-ray diffraction, resolution limit, 2.14 Å, PDB ID 6LTK, and their molecular interaction was analyzed in detail, which suggested that SNX-2112 was well accommodated in the ATP-binding pocket to disable molecular chaperone activity of Hsp90, therefore exhibiting favorable inhibiting activity on three non-small cell lung cancer (NSCLC) cell lines (IC, 0.50 ± 0.01 μM for A549, 1.14 ± 1.11 μM for H1299, 2.36 ± 0.82 μM for H1975) by inhibited proliferation, induced cell cycle arrest, and aggravated cell apoptosis. SNX-2112 exhibited high affinity and beneficial thermodynamic changes during the binding process with its target Hsp90 confirmed by thermal shift assay (TSA, ΔTm, and -9.51 ± 1.00°C) and isothermal titration calorimetry ( , 14.10 ± 1.60 nM). Based on the complex crystal structure and molecular interaction analysis, 32 novel SNX-2112 derivatives were designed, and 25 new ones displayed increased binding force with the target Hsp90 verified by molecular docking evaluation. The results would provide new references and guides for anti-NSCLC new drug development based on the lead compound SNX-2112.
SNX-2112作为一种有前景的靶向热休克蛋白90（Hsp90）的抗癌先导化合物，Hsp90与SNX-2112缺乏复杂晶体结构阻碍了进一步的结构优化和对分子相互作用机制的理解。在此，通过X射线衍射成功测定了Hsp90与SNX-2112的高分辨率复杂晶体结构，分辨率极限为2.14 Å，PDB ID为6LTK，并对它们的分子相互作用进行了详细分析，结果表明SNX-2112很好地容纳在ATP结合口袋中，使Hsp90的分子伴侣活性丧失，因此对三种非小细胞肺癌（NSCLC）细胞系表现出良好的抑制活性（对A549细胞的IC50为0.50±0.01 μM，对H1299细胞的IC50为1.14±1.11 μM，对H1975细胞的IC50为2.36±0.82 μM），通过抑制增殖、诱导细胞周期停滞和加剧细胞凋亡来实现。热迁移分析（TSA，ΔTm为-9.51±1.00°C）和等温滴定量热法（KD为14.10±1.60 nM）证实，SNX-2112在与靶标Hsp90的结合过程中表现出高亲和力和有利的热力学变化。基于复杂晶体结构和分子相互作用分析，设计了32种新型SNX-2112衍生物，其中25种新衍生物通过分子对接评估验证与靶标Hsp90的结合力增强。这些结果将为基于先导化合物SNX-2112的抗NSCLC新药开发提供新的参考和指导。
