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

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2013 Jun 26

PMID 23796364

Citations 71

Authors

Elena Miranda

Ida K Nordgren

Abigail L Male

Charlotte E Lawrence

Franciane Hoakwie

Francesco Cuda

William Court

Keith R Fox

Paul A Townsend

Graham K Packham

Suzanne A Eccles

Ali Tavassoli

Affiliations

Soon will be listed here.

Abstract

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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