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Structure and function of benzoylurea-derived alpha-helix mimetics targeting the Bcl-x(L)/Bak binding interface
Johanna M Rodriguez1, Nathan T Ross, William P Katt
1Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
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.
Insights
Novel benzoylurea compounds effectively inhibit the Bcl-x(L)/Bak interaction, a key target in cancer therapy. These alpha-helix mimetics disrupt apoptosis in cancer cells by binding to Bcl-x(L).
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- The interaction between B-cell lymphoma-extra large (Bcl-xL) and Bcl-2-associated X protein (Bak) is crucial for regulating apoptosis.
- Inhibiting this protein-protein interaction is a promising strategy for developing novel cancer therapeutics.
Purpose of the Study:
- To design and synthesize a new class of alpha-helix mimetics targeting the Bcl-xL/Bak interaction.
- To evaluate the efficacy of these novel compounds in disrupting the Bcl-xL/Bak complex.
Main Methods:
- Rational design of alpha-helix mimetics based on a benzoylurea scaffold.
- Synthesis and characterization of benzoylurea derivatives.
- Biophysical assays including fluorescence polarization competition, isothermal titration calorimetry, and (15)N-HSQC to assess binding to Bcl-xL.
Main Results:
- Novel benzoylurea derivatives were synthesized, exhibiting improved solubility and synthetic feasibility.
- These compounds mimic key residues of the Bak alpha-helix, binding to the hydrophobic pocket of Bcl-xL.
- Low micromolar inhibition and dissociation constants were observed, demonstrating effective disruption of the Bcl-xL/Bak interaction.
Conclusions:
- Benzoylurea-based alpha-helix mimetics represent a viable strategy for targeting the Bcl-xL/Bak interaction.
- These compounds show potential as therapeutic agents for inducing apoptosis in cancer cells.
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