Design, synthesis and bioevaluation of inhibitors targeting HSP90-CDC37 protein-protein interaction based on a hydrophobic core.
Design, synthesis and bioevaluation of inhibitors targeting HSP90-CDC37 protein-protein interaction based on a hydrophobic core.
复制标题
DOI：
10.1016/j.ejmech.2020.112959
复制
发表时间：
2020-10
影响因子：
6.7
通讯作者：
Qiuyue Zhang;Xuexuan Wu;Jianrui Zhou;Lixiao Zhang;Xiaoli Xu;Lianshan Zhang;Q. You;Lei Wang
中科院分区：
文献类型：
--
作者：
Qiuyue Zhang;Xuexuan Wu;Jianrui Zhou;Lixiao Zhang;Xiaoli Xu;Lianshan Zhang;Q. You;Lei Wang
HSP90-CDC37蛋白-蛋白相互作用(PPI)是一种蛋白特异性分子伴侣系统，调节蛋白激酶的成熟。目前，选择性地干扰HSP90-CDC37 PPI，而不是直接抑制HSP90的ATPase功能，正在成为一种有希望的癌症治疗策略，通过特异性地阻断激酶的成熟。然而，由于对HSP90-CDC37结合界面的了解有限，针对HSP90-CDC37 PPI的小分子抑制剂的设计是具有挑战性的。在这项工作中，基于化合物11的结合模式(本课题组先前报道)，我们发现了一个以Phe213为中心的疏水口袋，这是以前未知的，有助于HSP90-CDC37 PPI抑制剂的结合亲和力。利用一系列疏水取代的抑制剂证实了Phe213疏水核心的重要性。最终，我们得到了一个最佳的化合物DDO-5994(在疏水核心上表现出理想的结合模式)，其结合亲和力(Kd=55.52μM)和抗增殖活性(IC_(50)=66.34μM)得到了提高。活体实验证实DDO-5994是一种有希望通过阻断HSP90-CDC37 PPI而显示出理想的抗肿瘤效果的抑制剂。
HSP90-CDC37 protein-protein interaction (PPI) works as a kinase specific-molecular chaperone system to regulate the maturation of kinases. Currently, selectively disrupting HSP90-CDC37 PPI, rather than the direct inhibition of the ATPase function of HSP90, is emerging as a promising strategy for cancer therapy by specifically blocking the maturation of kinases. However, due to the limited understanding of HSP90-CDC37 binding interface, design of small molecule inhibitors targeting HSP90-CDC37 PPI is challenging. In this work, based on the binding mode ofcompound 11(previously reported by our group), we discovered a hydrophobic pocket centered on Phe213, which was previously unknown, contributing to the binding affinity of HSP90-CDC37 PPI inhibitors. A series of hydrophobic substituted inhibitors were utilized to confirm the importance of Phe213 hydrophobic core. Finally, we obtained an optimum compoundDDO-5994(exhibited an ideal binding pattern on hydrophobic core) with improved binding affinity (KD= 5.52μM) and antiproliferative activity (IC50= 6.34μM). Bothin vitroandin vivoassays confirmedDDO-5994as a promising inhibitor to exhibit ideal antitumor efficacy through blocking HSP90-CDC37 PPI.