Terephthalamide derivatives as mimetics of helical peptides: Disruption of the Bcl-xL/Bak interaction

Hang Yin, Gui In Lee, Kristine A. Sedey, Johanna M. Rodriguez, Hong Gang Wang, Said M. Sebti, Andrew D. Hamilton

Research output: Contribution to journalArticlepeer-review

Abstract

A series of Bcl-xL/Bak antagonists, based on a terephthalamide scaffold, was designed to mimic the α-helical region of the Bak peptide. These molecules showed favorable in vitro activities in disrupting the Bcl-xL/Bak BH3 domain complex (terephthalamides 9 and 26, K i = 0.78 ± 0.07 and 1.85 ± 0.32 μM, respectively). Extensive structure-affinity studies demonstrated a correlation between the ability of terephthalamide derivatives to disrupt Bcl-xL/Bak complex formation and the size of variable side chains on these molecules. Treatment of human HEK293 cells with the terephthalamide derivative 26 resulted in disruption of the Bcl-xL/Bax interaction in whole cells with an IC50 of 35.0 μM. Computational docking simulations and NMR experiments suggested that the binding cleft for the BH3 domain of the Bak peptide on the surface of Bcl-xL is the target area for these synthetic inhibitors.

Original languageEnglish (US)
Pages (from-to)5463-5468
Number of pages6
JournalJournal of the American Chemical Society
Volume127
Issue number15
DOIs
StatePublished - Apr 20 2005

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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