Zhang Qiuyue, Wu Xuexuan, Zhou Jianrui, Zhang Lixiao, Xu Xiaoli, Zhang Lianshan, You Qidong, Wang Lei
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Shanghai Hengrui Pharmaceutical Co., Ltd., Shanghai, 200245, China.
Eur J Med Chem. 2021 Jan 15;210:112959. doi: 10.1016/j.ejmech.2020.112959. Epub 2020 Oct 22.
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 of compound 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 compound DDO-5994 (exhibited an ideal binding pattern on hydrophobic core) with improved binding affinity (K = 5.52 μM) and antiproliferative activity (IC = 6.34 μM). Both in vitro and in vivo assays confirmed DDO-5994 as a promising inhibitor to exhibit ideal antitumor efficacy through blocking HSP90-CDC37 PPI.
热休克蛋白90（HSP90）-细胞分裂周期蛋白37（CDC37）蛋白-蛋白相互作用（PPI）作为一种激酶特异性分子伴侣系统，调节激酶的成熟。目前，选择性破坏HSP90-CDC37 PPI，而非直接抑制HSP90的ATP酶功能，正成为一种通过特异性阻断激酶成熟来治疗癌症的有前景的策略。然而，由于对HSP90-CDC37结合界面的了解有限，设计靶向HSP90-CDC37 PPI的小分子抑制剂具有挑战性。在这项工作中，基于化合物11（先前由我们小组报道）的结合模式，我们发现了一个以苯丙氨酸213为中心的疏水口袋，这是之前未知的，它有助于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来证实苯丙氨酸213疏水核心的重要性。最后，我们获得了一种最佳化合物DDO-5994（在疏水核心上表现出理想的结合模式），其结合亲和力（K = 5.52 μM）和抗增殖活性（IC = 6.34 μM）均有所提高。体外和体内试验均证实DDO-5994是一种有前景的抑制剂，可通过阻断HSP90-CDC37 PPI展现出理想的抗肿瘤疗效。
