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A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells

A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells
A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells
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.
0002-7863
10418-10425
Miranda, Elena
ad727f7b-cc62-4904-b46d-043f74ef88ed
Nordgren, Ida
f7d821ab-ba6c-4286-b439-f758909b2d61
Male, Abigail
cad6c2bc-04df-4078-b5d2-9f3c808e6152
Lawrence, Charlotte
90aa9115-672e-4474-964e-08c116fecb72
Hoakwie, Franciane
be6ab35d-4511-45ae-b059-32ae7b4236af
Cuda, F.
8c738a55-70a8-4063-b063-bf83cdf0f270
Court, William
7654c063-7848-4221-af2c-3539c517ae7b
Fox, Keith R.
9da5debc-4e45-473e-ab8c-550d1104659f
Townsend, Paul
54e7bb11-feba-4886-b792-ab0f93c9c734
Packham, Graham K.
fdabe56f-2c58-469c-aadf-38878f233394
Eccles, Suzanne A.
d75ea311-8425-435a-83c6-5928152e092f
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Miranda, Elena
ad727f7b-cc62-4904-b46d-043f74ef88ed
Nordgren, Ida
f7d821ab-ba6c-4286-b439-f758909b2d61
Male, Abigail
cad6c2bc-04df-4078-b5d2-9f3c808e6152
Lawrence, Charlotte
90aa9115-672e-4474-964e-08c116fecb72
Hoakwie, Franciane
be6ab35d-4511-45ae-b059-32ae7b4236af
Cuda, F.
8c738a55-70a8-4063-b063-bf83cdf0f270
Court, William
7654c063-7848-4221-af2c-3539c517ae7b
Fox, Keith R.
9da5debc-4e45-473e-ab8c-550d1104659f
Townsend, Paul
54e7bb11-feba-4886-b792-ab0f93c9c734
Packham, Graham K.
fdabe56f-2c58-469c-aadf-38878f233394
Eccles, Suzanne A.
d75ea311-8425-435a-83c6-5928152e092f
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Miranda, Elena, Nordgren, Ida, Male, Abigail, Lawrence, Charlotte, Hoakwie, Franciane, Cuda, F., Court, William, Fox, Keith R., Townsend, Paul, Packham, Graham K., Eccles, Suzanne A. and Tavassoli, Ali (2013) A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells. Journal of the American Chemical Society, 135 (28), 10418-10425. (doi:10.1021/ja402993u). (PMID:23796364)

Record type: Article

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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Published date: 24 June 2013
Organisations: Organic Chemistry: Synthesis, Catalysis and Flow

Identifiers

Local EPrints ID: 354176
URI: http://eprints.soton.ac.uk/id/eprint/354176
ISSN: 0002-7863
PURE UUID: 3430f913-687c-401a-8ab8-700f67127022
ORCID for Keith R. Fox: ORCID iD orcid.org/0000-0002-2925-7315
ORCID for Graham K. Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

Catalogue record

Date deposited: 03 Jul 2013 11:45
Last modified: 26 Nov 2019 02:07

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