Epidithiodiketopiperazines block the interaction between hypoxia-inducible factor-1α (HIF-1α) and p300 by a zinc ejection mechanism

Kristina M. Cook, Stephen T. Hilton, Jasmin Mecinovic, William B. Motherwell, William D. Figg*, Christopher J. Schofield

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

157 Scopus citations

Abstract

The hypoxic response in humans is regulated by the hypoxiainducible transcription factor system; inhibition of hypoxia-inducible factor (HIF) activity has potential for the treatment of cancer. Chetomin, a member of the epidithiodiketopiperazine (ETP) family of natural products, inhibits the interaction between HIF-α and the transcriptional coactivator p300. Structure-activity studies employing both natural and synthetic ETP derivatives reveal that only the structurally unique ETP core is required and sufficient to block the interaction of HIF-1α and p300. In support of both cell-based and animal work showing that the cytotoxic effect of ETPs is reduced by the addition of Zn2+ through an unknown mechanism, our mechanistic studies reveal that ETPs react with p300, causing zinc ion ejection. Cell studies with both natural and synthetic ETPs demonstrated a decrease in vascular endothelial growth factor and antiproliferative effects that were abrogated by zinc supplementation. The results have implications for the design of selective ETPs and for the interaction of ETPs with other zinc ion-binding protein targets involved in gene expression.

Original languageEnglish
Pages (from-to)26831-26838
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number39
DOIs
StatePublished - 25 Sep 2009
Externally publishedYes

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