Structure-based virtual screening, biological evaluation and biophysical study of novel Mcl-1 inhibitors

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作者单位: Affiliations ¹ Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250117, PR China. ² Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, PR China. ³ Department of Medicinal Chemistry & Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.

关键词: Mcl-1 inhibitor anticancer apoptosis protein–protein interactions virtual screening.

摘要: Aim: Targeting the protein-protein interactions associated with Mcl-1 has become a promising therapeutic approach for cancer. Herein, we reported the discovery of novel Mcl-1 inhibitors using an integrated computational approach. Results: Among 30 virtual screening hits, five compounds show inhibitory activities against Mcl-1. The most potent inhibitors M02 and M08 exhibit good selectivity against Bcl-2 and Bcl-xL. Compound M08 exhibits anti-proliferation activity and induces caspase-3 activa...更多; Aim: Targeting the protein-protein interactions associated with Mcl-1 has become a promising therapeutic approach for cancer. Herein, we reported the discovery of novel Mcl-1 inhibitors using an integrated computational approach. Results: Among 30 virtual screening hits, five compounds show inhibitory activities against Mcl-1. The most potent inhibitors M02 and M08 exhibit good selectivity against Bcl-2 and Bcl-xL. Compound M08 exhibits anti-proliferation activity and induces caspase-3 activation in Jurkat cancer cells. Moreover, H⁄N HSQC NMR experiments suggested that compound M08 likely binds in the P2 pocket of Mcl-1 and engages R263 in a salt bridge. Conclusion: Our study provides a good starting point for future discovery of more potent Mcl-1 selective inhibitors.收起

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