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Structure and Function of Benzoylurea‐Derived α‐Helix Mimetics Targeting the Bcl‐x L /Bak Binding Interface
Author(s) -
Rodriguez Johanna M.,
Ross Nathan T.,
Katt William P.,
Dhar Deepali,
Lee Guiin,
Hamilton Andrew D.
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800387
Subject(s) - chemistry , function (biology) , helix (gastropod) , biophysics , biology , microbiology and biotechnology , ecology , snail
Targeting Bcl‐x L /Bak : A family of rationally designed α‐helix mimetics with improved solubility and synthetic feasibility based on a benzoylurea scaffold is presented. 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 α‐helix. Binding affinities of the benzoylurea derivatives to Bcl‐x L have been assessed using fluorescence polarization competition assays and isothermal titration calorimetry.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 α ‐helix, into a hydrophobic cleft on Bcl‐x L . 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 an α‐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.