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). 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.
School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT (UK); Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT (UK).
George M
GM
Burslem
Hannah F
HF
Kyle
Alexander L
AL
Breeze
Thomas A
TA
Edwards
Adam
A
Nelson
Stuart L
SL
Warriner
Andrew J
AJ
Wilson
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D032701:Biomimetics; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D050881:E1A-Associated p300 Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000577:Amides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D054852:Small Molecule Libraries; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
helix mimetics; hypoxia; inhibitors; peptidomimetics; protein-protein interactions