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

Authors
  • Du, Jintong1, 2
  • Liu, Lulu3
  • Liu, Bo2
  • Yang, Jing2
  • Hou, Xuben3
  • Yu, Jinming2
  • Fang, Hao3
  • 1 Shandong Cancer Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250117, PR China. , (China)
  • 2 Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, PR China. , (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. , (China)
Type
Published Article
Journal
Future Medicinal Chemistry
Publisher
"Future Science, LTD"
Publication Date
Jul 01, 2020
Volume
12
Issue
14
Pages
1293–1304
Identifiers
DOI: 10.4155/fmc-2020-0114
PMID: 32397829
Source
Medline
Keywords
Language
English
License
Unknown

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 (K i = 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.

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