Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-1

Chengguo Xing, Liangyou Wang, Xiao Hu Tang, Yuk Y. Sham

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

A series of inhibitors for anti-apoptotic Bcl-2 proteins based on BHI-1 were synthesized and their binding interactions with Bcl-2, Bcl-XL, and Bcl-w were evaluated. It was found that modification of BHI-1 resulted in varied binding profiles among Bcl-2, Bcl-XL, and Bcl-w, and a set of inhibitors with varied selectivity to Bcl-2, Bcl-XL, and Bcl-w proteins have been identified. Molecular modeling of the interaction of the BHI-1 based analogues with the anti-apoptotic Bcl-2 proteins suggested that the binding site for the BHI-1 based inhibitor was the least conserved section among Bcl-2, Bcl-XL, and Bcl-w: targeting the non-conserved section may account for the observed selectivity of the BHI-1 based inhibitors among the anti-apoptotic Bcl-2 proteins. The validity of the model was supported by a strong correlation between the model-calculated binding energy and the experimental binding affinity. In summary, our studies suggest that most of the reported inhibitors for anti-apoptotic Bcl-2 proteins are nonselective and BHI-1 is a promising template to distinguish among Bcl-2, Bcl-XL, and Bcl-w by targeting the non-conserved domain among the anti-apoptotic Bcl-2 proteins. Molecular-modeling-aided rational development of BHI-1 based selective inhibitor for anti-apoptotic Bcl-2 proteins is underway.

Original languageEnglish (US)
Pages (from-to)2167-2176
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number5
DOIs
StatePublished - Mar 1 2007

Keywords

  • Apoptosis
  • Bcl-2
  • Inhibitor
  • Selectivity

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