In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics

• DOI: 10.1073/pnas.1402393111
• Publication Date: 2014-05-13T08:53:58Z
• Authors: Brooke Bullock Lao; Ivan Grishagin; Hanah Mesallati; Thomas F. Brewer; Bogdan Z. Olenyuk; Paramjit S. Arora
• Keywords: 0301 basic medicine; Molecular Structure; Gene Expression Profiling; Blotting, Western; Molecular Sequence Data; Hypoxia-Inducible Factor 1, alpha Subunit; Piperazines; 3. Good health; Small Molecule Libraries; Mice; 03 medical and health sciences; Biomimetics; Mutagenesis; Drug Discovery; Animals; Protein Interaction Domains and Motifs; p300-CBP Transcription Factors; Amino Acid Sequence; Anaerobiosis; Cloning, Molecular; Luciferases; Piperazine

Significance Protein–protein interactions are attractive targets for drug design due to their fundamental role in biological function. However, small molecules that selectively target the intended interactions have been difficult to access using traditional drug discovery approaches. We show that compounds that reproduce key functionality at the interface between transcription factor hypoxia-inducible factor 1α (HIF1α) and coactivator p300 (or CREB binding protein, CBP) can inhibit expression of a multitude of genes under hypoxic environments. The designed inhibitors target the chosen protein–protein interaction in a predictable manner and reduce tumor growth in mouse xenograft models.