Sanchez-Martin Carlos, Moroni Elisabetta, Ferraro Mariarosaria, Laquatra Claudio, Cannino Giuseppe, Masgras Ionica, Negro Alessandro, Quadrelli Paolo, Rasola Andrea, Colombo Giorgio
Dipartimento di Scienze Biomediche, Università di Padova, viale G. Colombo 3, 35131 Padova, Italy.
Istituto di Scienze e Tecnologie Chimiche "Giulio Natta"-SCITEC, Via Mario Bianco 9, 20131 Milano, Italy.
Cell Rep. 2020 Apr 21;31(3):107531. doi: 10.1016/j.celrep.2020.107531.
TRAP1 is the mitochondrial paralog of the heat shock protein 90 (HSP90) chaperone family. Its activity as an energy metabolism regulator has important implications in cancer, neurodegeneration, and ischemia. Selective inhibitors of TRAP1 could inform on its mechanisms of action and set the stage for targeted drug development, but their identification was hampered by the similarity among active sites in HSP90 homologs. We use a dynamics-based approach to identify a TRAP1 allosteric pocket distal to its active site that can host drug-like molecules, and we select small molecules with optimal stereochemical features to target the pocket. These leads inhibit TRAP1, but not HSP90, ATPase activity and revert TRAP1-dependent downregulation of succinate dehydrogenase activity in cancer cells and in zebrafish larvae. TRAP1 inhibitors are not toxic per se, but they abolish tumorigenic growth of neoplastic cells. Our results indicate that exploiting conformational dynamics can expand the chemical space of chaperone antagonists to TRAP1-specific inhibitors with wide therapeutic opportunities.
TRAP1是热休克蛋白90（HSP90）伴侣家族的线粒体旁系同源物。其作为能量代谢调节剂的活性在癌症、神经退行性变和局部缺血中具有重要意义。TRAP1的选择性抑制剂可以揭示其作用机制，并为靶向药物开发奠定基础，但其鉴定受到HSP90同源物活性位点相似性的阻碍。我们采用基于动力学的方法，在TRAP1活性位点远端鉴定出一个可容纳类药物分子的变构口袋，并选择具有最佳立体化学特征的小分子靶向该口袋。这些先导化合物可抑制TRAP1而非HSP90的ATP酶活性，并逆转癌细胞和斑马鱼幼虫中TRAP1依赖性的琥珀酸脱氢酶活性下调。TRAP1抑制剂本身无毒，但可消除肿瘤细胞的致瘤生长。我们的结果表明，利用构象动力学可以将伴侣拮抗剂的化学空间扩展为具有广泛治疗机会的TRAP1特异性抑制剂。
