Structure and function of benzoy Iurea-derived A-helix mimetics targeting the Bcl-xL/bak binding interface

Johanna M. Rodriguez, Nathan T. Ross, William P. Katt, Deepali Dhar, Gui in Lee, Andrew D. Hamilton

Research output: Contribution to journalArticlepeer-review


The Bel-xLBak protein-protein interaction has emerged as an important target for cancer therapy due to its role in apopto-sis. 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, 181, and 185), corresponding to the i, i+4, i+7, and i+11 positions of an α-helix, into a hydrophobic cleft on Bcl-xL. Herein, we present a novel family of rationally designed α-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 and α-helix. The binding of the benzoylurea derivatives to Bcl-xLwas assessed using fluorescence polarization competition assays, isothermal titration calorimetry, and "N-HSQC experiments. These experiments showed that these agents bind to and disrupt Bcl-xL with low micromolar inhibition and dissociation constants, with 15N-HSQC experiments confirming binding to the hydrophobic pocket of Bcl-xL normally occupied by the Bak helix.

Original languageEnglish (US)
Pages (from-to)649-656
Number of pages8
Issue number4
StatePublished - Apr 17 2009


  • Bcl-x
  • Calorimetry
  • Protiein-protiein interactionsn benzoylurea scaffold
  • α-helix mimetics

ASJC Scopus subject areas

  • Drug Discovery
  • General Pharmacology, Toxicology and Pharmaceutics
  • Molecular Medicine
  • Biochemistry
  • Pharmacology
  • Organic Chemistry


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