Journal of the American Chemical Society · 2013 · 185 citations · 38 references
Cancer BiologyCyclic Peptide InhibitorTumor BiologyOxidative StressRedox RegulatorCancer Cell BiologyAnti-cancer AgentCancer MetabolismCell SignalingMolecular OncologyCancer ResearchHeterodimeric Transcription FactorHypoxia (Medicine)Cancer CellsPharmacologyCell BiologyTumor MicroenvironmentInhibits Hypoxia SignalingCyclic PeptideTumor SuppressorSystems BiologyMedicineCyclic HexapeptidesSmall Molecules
Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that acts as the master regulator of cellular response to reduced oxygen levels, thus playing a key role in the adaptation, survival, and progression of tumors. Here we report cyclo-CLLFVY, identified from a library of 3.2 million cyclic hexapeptides using a genetically encoded high-throughput screening platform, as an inhibitor of the HIF-1α/HIF-1β protein-protein interaction in vitro and in cells. The identified compound inhibits HIF-1 dimerization and transcription activity by binding to the PAS-B domain of HIF-1α, reducing HIF-1-mediated hypoxia response signaling in a variety of cell lines, without affecting the function of the closely related HIF-2 isoform. The reported cyclic peptide demonstrates the utility of our high-throughput screening platform for the identification of protein-protein interaction inhibitors, and forms the starting point for the development of HIF-1 targeted cancer therapeutics.
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