title: Terephthalamide derivatives as mimetics of helical peptides: disruption of the Bcl-x(L)/Bak interaction.
abstract: A series of Bcl-x(L)/Bak antagonists, based on a terephthalamide scaffold, was designed to mimic the alpha-helical region of the Bak peptide. These molecules showed favorable in vitro activities in disrupting the Bcl-x(L)/Bak BH3 domain complex (terephthalamides 9 and 26, K(i) = 0.78 +/- 0.07 and 1.85 +/- 0.32 microM, respectively). Extensive structure-affinity studies demonstrated a correlation between the ability of terephthalamide derivatives to disrupt Bcl-x(L)/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-x(L)/Bax interaction in whole cells with an IC(50) of 35.0 microM. Computational docking simulations and NMR experiments suggested that the binding cleft for the BH3 domain of the Bak peptide on the surface of Bcl-x(L) is the target area for these synthetic inhibitors.
authors.affiliation: Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
authors.forename: Gui-In
authors.initials: GI
authors.lastname: Lee
authors.forename: Kristine A
authors.initials: KA
authors.lastname: Sedey
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rodriguez
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D005454:Fluorescence Polarization; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010797:Phthalimides / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D008565:Membrane Proteins; D010797:Phthalimides; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C047750:terephthalamidine