A Cyclic Peptide Inhibitor of HIF‑1 Heterodimerization That Inhibits Hypoxia Signaling in Cancer Cells

• Published in: Journal of the American Chemical Society 2013-07, Vol.135 (28), p.10418-10425
• Main Authors: Miranda, Elena, Nordgren, Ida K, Male, Abigail L, Lawrence, Charlotte E, Hoakwie, Franciane, Cuda, Francesco, Court, William, Fox, Keith R, Townsend, Paul A, Packham, Graham K, Eccles, Suzanne A, Tavassoli, Ali
• Format: Article
• Language: English
• Subjects: Aryl Hydrocarbon Receptor Nuclear Translocator - antagonists & inhibitors; Cancer; Cell Line, Tumor; Cellular; Dimerization; Dose-Response Relationship, Drug; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Inhibitors; MCF-7 Cells; Peptides; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Platforms; Screening; Signal Transduction - drug effects; Structure-Activity Relationship
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja402993u

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.