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Research Article

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

    Jintong Du

    Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250117, PR China

    Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, PR China

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    ,
    Lulu Liu

    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

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    ,
    Bo Liu

    Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, PR China

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    ,
    Jing Yang

    Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, PR China

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    ,
    Xuben Hou

    *Author for correspondence:

    E-mail Address: hxb@sdu.edu.cn

    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

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    ,
    Jinming Yu

    **Author for correspondence:

    E-mail Address: sdyujinming@163.com

    Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, PR China

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    &
    Hao Fang

    ***Author for correspondence:

    E-mail Address: haofangcn@sdu.edu.cn

    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

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    Published Online:13 May 2020https://doi.org/10.4155/fmc-2020-0114

    Abstract

    Aim: Targeting the protein–protein interactions (PPIs) 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 (Ki = 5.4 μM) and M08 (Ki = 0.53 μM) 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, 1H⁄15N 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.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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