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

作者：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^*

来源：Journal of the American Chemical Society, 2013, 135(28): 10418-10425.

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 HIP-1 alpha/HIF-1 beta 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-1 alpha, 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.

• 出版日期2013-7-17