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 journalArticle

123 Citations (Scopus)

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

Fingerprint

HEK293 Cells
Peptides
Inhibitory Concentration 50
Derivatives
Molecules
Scaffolds
Nuclear magnetic resonance
Experiments
In Vitro Techniques
Protein Domains

All Science Journal Classification (ASJC) codes

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

Cite this

Yin, Hang ; Lee, Gui In ; Sedey, Kristine A. ; Rodriguez, Johanna M. ; Wang, Hong-Gang ; Sebti, Said M. ; Hamilton, Andrew D. / Terephthalamide derivatives as mimetics of helical peptides : Disruption of the Bcl-xL/Bak interaction. In: Journal of the American Chemical Society. 2005 ; Vol. 127, No. 15. pp. 5463-5468.
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Terephthalamide derivatives as mimetics of helical peptides : Disruption of the Bcl-xL/Bak interaction. / Yin, Hang; Lee, Gui In; Sedey, Kristine A.; Rodriguez, Johanna M.; Wang, Hong-Gang; Sebti, Said M.; Hamilton, Andrew D.

In: Journal of the American Chemical Society, Vol. 127, No. 15, 20.04.2005, p. 5463-5468.

Research output: Contribution to journalArticle

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