title: Structure and function of benzoylurea-derived alpha-helix mimetics targeting the Bcl-x(L)/Bak binding interface.
abstract: The Bcl-x(L)/Bak protein-protein interaction has emerged as an important target for cancer therapy due to its role in apoptosis. Inhibition of this interaction by small-molecule antagonists induces apoptosis in unhealthy cells. Bak, a pro-apoptotic Bcl-2 protein, projects four hydrophobic side chains (V74, L78, I81, and I85), corresponding to the i, i+4, i+7, and i+11 positions of an alpha-helix, into a hydrophobic cleft on Bcl-x(L). Herein, we present a novel family of rationally designed alpha-helix mimetics with improved solubility and synthetic feasibility based on a benzoylurea scaffold. These benzoylurea derivatives favor a linear conformation stabilized by an intramolecular hydrogen bond, and are able to mimic the spatial projection of the i, i+4, and i+7 residues of an alpha-helix. The binding of the benzoylurea derivatives to Bcl-x(L) was assessed using fluorescence polarization competition assays, isothermal titration calorimetry, and (15)N-HSQC experiments. These experiments showed that these agents bind to and disrupt Bcl-x(L) with low micromolar inhibition and dissociation constants, with (15)N-HSQC experiments confirming binding to the hydrophobic pocket of Bcl-x(L) normally occupied by the Bak helix.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rodriguez
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Ross
authors.forename: William P
authors.initials: WP
authors.lastname: Katt
authors.forename: Deepali
authors.initials: D
authors.lastname: Dhar
authors.forename: Gui-In
authors.initials: GI
authors.lastname: Lee
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton