2. Academic Validation
  3. Design, synthesis, and activity evaluation of selective inhibitors of anti-apoptotic Bcl-2 proteins: The effects on the selectivity of the P1 pockets in the active sites

Design, synthesis, and activity evaluation of selective inhibitors of anti-apoptotic Bcl-2 proteins: The effects on the selectivity of the P1 pockets in the active sites

  • Bioorg Med Chem Lett. 2016 Nov 1;26(21):5207-5211. doi: 10.1016/j.bmcl.2016.09.061.
Mingping Wang 1,  Wei Tian 2,  Chongqing Wang 2,  Shihai Lu 2,  Chao Yang 2,  Juan Wang 3,  Yunlong Song 2,  Youjun Zhou 2,  Ju Zhu 4,  Zhiyu Li 5,  Canhui Zheng 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 2 School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 3 Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, China.
  • 4 School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: [email protected].
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: [email protected].
  • 6 School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: [email protected].
PMID: 27712939 DOI: 10.1016/j.bmcl.2016.09.061
Abstract

The anti-apoptotic Bcl-2 proteins are attractive targets for anti-cancer drug development, and the discovery of their selective inhibitors has become a research focus. In this Letter, obvious differences in the P1 pocket of the active site between Bcl-2, Bcl-xL, and Mcl-1 proteins were proposed by the structural comparison of these proteins. As a result, the groups in their inhibitors binding to the P1 pockets may have significant effect on the selectivity for these proteins. Based on this hypothesis, five types of derivatives of the lead compound B-1 were designed, and several highly selective inhibitors of Bcl-xL (E-1) or Mcl-1 proteins (G) were found. The selective inhibitors of Mcl-1 protein found in this Letter provide new structural types for the development of novel antitumor agents.

Keywords

Anti-apoptotic Bcl-2 proteins; Anti-tumor; Mcl-1 protein; Selective inhibitors.

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