ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; School of Medicine, Zhejiang University City College, Hangzhou, 310015, China.
Eur J Med Chem. 2019 Feb 15;164:602-614. doi: 10.1016/j.ejmech.2018.12.064. Epub 2018 Dec 26.
The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event. Compound 1 composed of a six-membered heterocyclic ring was designed by using covalent docking. With a possible different binding mode from the clinical compound Carfilzomib, it occupied the S5 pocket of 20S proteasome and showed favorable inhibitory activity. Subsequently optimization and evaluation were taken place. Among these compounds, 11h demonstrated extraordinary in vitro inhibitory activity and selectivity, and good in vivo proteasome inhibitory activity, a favorable pharmacokinetic profile and xenograft tumor inhibition. The possible binding pattern of compound 11h against proteasome was further fully explored via calculations, providing a theoretical basis for finding potent proteasome inhibitors.
特定蛋白酶体抑制剂作为抗癌药物的潜力引起了广泛的研究。蛋白酶体可以通过两步反应与环氧酮衍生物共价抑制。已经开发了几种计算方法来模拟共价结合事件。通过共价对接设计了由六元杂环组成的化合物 1。与临床化合物卡非佐米可能具有不同的结合模式，它占据了 20S 蛋白酶体的 S5 口袋，并表现出良好的抑制活性。随后进行了优化和评估。在这些化合物中，11h 表现出非凡的体外抑制活性和选择性，以及良好的体内蛋白酶体抑制活性、良好的药代动力学特征和异种移植肿瘤抑制作用。通过计算进一步充分探索了化合物 11h 与蛋白酶体的可能结合模式，为寻找有效的蛋白酶体抑制剂提供了理论依据。
