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Small-molecule proteomimetic inhibitors of the HIF-1?-p300 protein-protein interaction.

ABSTRACT: The therapeutically relevant hypoxia inducible factor HIF-1?-p300 protein-protein interaction can be orthosterically inhibited with ?-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C-terminal helix of the HIF-1? 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-1?-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-1?, the result is still remarkable in that the mimetic reproduces only three residues from the 42-residue HIF-1? C-TAD from which it is derived.

SUBMITTER: Burslem GM

PROVIDER: S-EPMC4159589 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Small-molecule proteomimetic inhibitors of the HIF-1α-p300 protein-protein interaction.

Burslem George M GM Kyle Hannah F HF Breeze Alexander L AL Edwards Thomas A TA Nelson Adam A Warriner Stuart L SL Wilson Andrew J AJ

Chembiochem : a European journal of chemical biology 20140429 8

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 characteris ...[more]

PMID: 24782431

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