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

被引：155

作者：

Miranda, Elena ^{[1
]}

Nordgren, Ida K. ^{[1
]}

Male, Abigail L. ^{[1
]}

Lawrence, Charlotte E. ^{[1
]}

Hoakwie, Franciane ^{[1
]}

Cuda, Francesco ^{[1
]}

Court, William ^{[4
]}

Fox, Keith R. ^{[2
,3
]}

Townsend, Paul A. ^{[3
,5
]}

Packham, Graham K. ^{[3
,5
]}

Eccles, Suzanne A. ^{[4
]}

Tavassoli, Ali ^{[1
,3
,5
]}

机构：

[1] Univ Southampton, Southampton SO17 1BJ, Hants, England

[2] Univ Southampton, Ctr Biol Sci, Southampton SO17 1BJ, Hants, England

[3] Univ Southampton, Inst Life Sci, Southampton SO17 1BJ, Hants, England

[4] Inst Canc Res, Canc Res UK Canc Therapeut Unit, Sutton SM2 5NG, Surrey, England

[5] Univ Southampton, Fac Med, Southampton SO16 6YD, Hants, England

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2013年 / 135卷 / 28期

基金：

英国生物技术与生命科学研究理事会;

关键词：

INDUCIBLE FACTOR-I; SMALL-MOLECULE INHIBITORS; AICAR TRANSFORMYLASE HOMODIMERIZATION; TUMOR-GROWTH; BINDING-PROTEIN; HIF-1-ALPHA; INDUCTION; FACTOR-1; THERAPY; IDENTIFICATION;

D O I：

10.1021/ja402993u

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：10418 / 10425

页数：8

共 46 条

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