Development of dimeric modulators for anti-apoptotic Bcl-2 proteins

Liangyou Wang, Fansen Kong, Candis L. Kokoski, David W. Andrews, Chengguo Xing

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Bcl-2 family proteins can be classified into two subfamilies-anti-apoptotic members and pro-apoptotic members. Mechanistically, these two subfamilies can antagonize each other through heterodimerization while homodimerization has been proposed for each subfamily to carry out their corresponding anti-apoptotic or pro-apoptotic functions. To date, many small-molecule antagonists against anti-apoptotic Bcl-2 proteins have been developed, which are monomeric modulators. In this study, a series of BH3I-1 based dimeric modulators were developed with structure-activity relationship explored. Dimeric modulators compared to the monomeric antagonists have enhanced binding activity against anti-apoptotic Bcl-2 proteins. In addition, the acidic functional group was demonstrated to be critical for the binding interaction of the small-molecule antagonists with anti-apoptotic Bcl-2 proteins. Finally, the representative dimeric modulator revealed enhanced activity in inducing cytochrome c release from mitochondria compared to its monomeric counterpart. Taken together, dimerization of monomeric modulators is one practical approach to enhance the bioactivity of Bcl-2 antagonists.

Original languageEnglish (US)
Pages (from-to)236-240
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number1
StatePublished - Jan 1 2008
Externally publishedYes


  • Antagonist
  • Apoptosis
  • BH3I-1
  • Bcl-2
  • Dimeric
  • Modulator
  • Monomeric
  • Potency


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