靶向Hsp90-Cdc37蛋白-蛋白相互作用小分子抑制剂的研究进展

Advances in small-molecule inhibitors targeting Hsp90-Cdc37 proteinprotein interaction

热休克蛋白90(Hsp90)参与肿瘤生理与病理的多个过程,设计与开发有效的Hsp90抑制剂一直是抗肿瘤药物研发的热点。目前,传统的N端抑制剂的研发正处于瓶颈期,C端抑制剂的发展也受到了限制,阻碍Hsp90与细胞分裂周期蛋白Cdc37的相互作用已经成为了抑制Hsp90的全新方向。研究表明,很多的蛋白激酶需要依靠Cdc37而聚集到Hsp90上,从而完成空间构象的正确折叠。因此,靶向Hsp90-Cdc37能够具有针对性地抑制Hsp90的激酶类客户蛋白,降低不良反应。随着对Hsp90与Cdc37相互作用机制越来越深入的研究,很多能够干扰Hsp90-Cdc37的天然产物被发现,本文从发现过程、作用机制这两方面综述这些小分子抑制剂的研究进展。

Heat shock protein 90 （Hsp90） which is a molecular chaperone that integrates multiple oncogenic pathways, is an important target in cancer therapy. The present research and development of the traditional N-ter- minal and C-terminal inhibitors has been restricted while targeting Hsp90 and cell division cycle protein Cdc37 has become the new direction of inhibiting Hsp90. Previous studies have demonstrated that various protein kinases rely on Cdc37 to load onto Hsp90 to complete their correct folding. Thus targeting Hsp90-Cdc37 is a promising strategy to inhibit protein kinases and alleviate the side effects. The interaction mechanism between Hsp90 and Cdc37 has become clearer in recent studies and many natural products have been reported to possess the ability to disassociate Hsp90-Cdc37. In this review, current knowledge on these small molecule inhibitors are summa- rized. The mode of action is also discussed as the references for the development of novel HsD90 inhibitors.