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

Abstract

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.

FOXO3–NF-κB RelA Protein Complexes Reduce Proinflammatory Cell Signaling and Function

“…One avenue to target such interactions is the development of small molecule inhibitors that can be targeted to specific cell populations by the use of a defined antigen tag, as seen with DEC-205 for targeting dendritic cells (33). Small molecule or kinase inhibitors have primarily been used to treat tumors directly such as MAPK, HIF-1a-p300, FAK-VEGFR3 and many others (34-36). The use of small molecules may be ideal to enhance current immune therapies in terms of both efficiency and duration of effect.…”

Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein–protein interactions

“…Because they are easily prepared by a modular synthesis and have improved water solubility [32,33], aromatic oligoamides are an attractive scaffold and widely utilized as a-helix mimetics [32,[34][35][36][37][38][39][40][41]. For example, recently, Wilson and co-workers have utilized trisbenzamides as an a-helix mimetic scaffold to develop inhibitors of the interaction between hypoxia inducible factor-1a (HIF-1a) and p300 [39 ]. Given that the C-terminal transcription domain of HIF-1a adopts a helical conformation for interacting with p300, a-helix mimetics approach should be a promising strategy to discover inhibitors of the interaction as demonstrated by Arora and co-workers [42].…”

Helix mimetics: Recent developments

“…Although it is natural to develop new methodologies on tried and trusted model systems, this should change and several recent studies provide encouragement. Inhibitors of HIF-1a/p300 (Lao et al, 2014a(Lao et al, , 2014bBurslem et al, 2014), ER/co-activator, (Becerril and Hamilton, 2007;Ravindranathan et al, 2013) (Martucci et al, 2013) and amyloid aggregation (hIAPP) (Hebda et al, 2009) have been described. The hIAPP aggregation inhibitors have an unusual mode of action in that they are proposed to sequester a helical intermediate en route to the bstrand conformer that assembles into b-sheet fibrils.…”

“…Similarly the O-alkylated aromatic oligoamide scaffold was shown to be capable of selective recognition (Fig. 5c); the HIF-1a inhibitors discussed above were incapable of inhibiting the eIF4E/4G interaction (Burslem et al, 2014). One of the most recent studies by the Wilson group focused on a "hybrid" helix mimetic comprising p-aminobenzoic acid and amino acid building blocks (Fig.…”