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Small-Molecule Proteomimetic Inhibitors of the HIF-1α–p300 Protein–Protein Interaction

The therapeutically relevant hypoxia inducible factor HIF-1α–p300 protein–protein interaction can be orthosterically inhibited with α-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C-terminal helix of the HIF-1α C-TAD (C-terminal transactivation domain)....

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Detalles Bibliográficos
Autores principales: Burslem, George M, Kyle, Hannah F, Breeze, Alexander L, Edwards, Thomas A, Nelson, Adam, Warriner, Stuart L, Wilson, Andrew J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159589/
https://www.ncbi.nlm.nih.gov/pubmed/24782431
http://dx.doi.org/10.1002/cbic.201400009
Descripción
Sumario:The therapeutically relevant hypoxia inducible factor HIF-1α–p300 protein–protein interaction can be orthosterically inhibited with α-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C-terminal helix of the HIF-1α C-TAD (C-terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side-chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characterised HIF-1α–p300 PPI inhibitors and the first examples of small-molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile. Although the compounds were less potent than HIF-1α, the result is still remarkable in that the mimetic reproduces only three residues from the 42-residue HIF-1α C-TAD from which it is derived.