Identification and development of cyclic peptide inhibitors of Hypoxia Inducible Factors 1 and 2 that disrupt hypoxia-response signaling in cancer cells

Abstract

Hypoxia inducible factor (HIF) is a heterodimeric transcription factor composed of an oxygen- regulated α subunit and a constitutively expressed β subunit that serves as the master regulator of the cellular response to low oxygen concentrations. The HIF transcription factor senses and responds to hypoxia by significantly altering transcription, reprogramming cells to enable survival and growth in the hypoxic tumor microenvironment. Given the central role played by HIF in the survival and growth of tumors in a hypoxic microenvironment, inhibition of this transcription factor serves as a potential therapeutic approach for treating a variety of cancers. Here, we report the identification, optimisation and characterisation of a series of cyclic peptides that disrupt the function of HIF-1 and HIF-2 transcription factors by inhibiting the interaction of both HIF-1α and HIF-2α with HIF-1β. The resulting compounds are shown to bind HIF and disrupt the protein-protein interaction between the α and β subunit of the transcription factor, resulting in disruption of hypoxia-response signaling in several cancer cell lines.

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Identifiers

ORCID for Soran Mohammed: orcid.org/0000-0002-3882-6129

ORCID for Steven Turner: orcid.org/0000-0002-2913-7532

ORCID for Jonathan W. Essex: orcid.org/0000-0003-2639-2746

ORCID for Ali Tavassoli: orcid.org/0000-0002-7420-5063

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