Structure and function of benzoylurea-derived alpha-helix mimetics targeting the Bcl-x(L)/Bak binding interface.
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 chain...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2009
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| _version_ | 1797070856524922880 |
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| author | Rodriguez, J Ross, N Katt, W Dhar, D Lee, G Hamilton, A |
| author_facet | Rodriguez, J Ross, N Katt, W Dhar, D Lee, G Hamilton, A |
| author_sort | Rodriguez, J |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:45:00Z |
| format | Journal article |
| id | oxford-uuid:5cdd1506-427e-4efc-ac39-6a7660be627a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:45:00Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:5cdd1506-427e-4efc-ac39-6a7660be627a2022-03-26T17:30:51ZStructure and function of benzoylurea-derived alpha-helix mimetics targeting the Bcl-x(L)/Bak binding interface.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5cdd1506-427e-4efc-ac39-6a7660be627aEnglishSymplectic Elements at Oxford2009Rodriguez, JRoss, NKatt, WDhar, DLee, GHamilton, AThe 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. |
| spellingShingle | Rodriguez, J Ross, N Katt, W Dhar, D Lee, G Hamilton, A Structure and function of benzoylurea-derived alpha-helix mimetics targeting the Bcl-x(L)/Bak binding interface. |
| title | Structure and function of benzoylurea-derived alpha-helix mimetics targeting the Bcl-x(L)/Bak binding interface. |
| title_full | Structure and function of benzoylurea-derived alpha-helix mimetics targeting the Bcl-x(L)/Bak binding interface. |
| title_fullStr | Structure and function of benzoylurea-derived alpha-helix mimetics targeting the Bcl-x(L)/Bak binding interface. |
| title_full_unstemmed | Structure and function of benzoylurea-derived alpha-helix mimetics targeting the Bcl-x(L)/Bak binding interface. |
| title_short | Structure and function of benzoylurea-derived alpha-helix mimetics targeting the Bcl-x(L)/Bak binding interface. |
| title_sort | structure and function of benzoylurea derived alpha helix mimetics targeting the bcl x l bak binding interface |
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