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Epidithiodiketopiperazines Block the Interaction between Hypoxia-inducible Factor-1 alpha (HIF-1 alpha) and p300 by a Zinc Ejection Mechanism

Cook, KM; Hilton, ST; Mecinovic, J; Motherwell, WB; Figg, WD; Schofield, CJ; (2009) Epidithiodiketopiperazines Block the Interaction between Hypoxia-inducible Factor-1 alpha (HIF-1 alpha) and p300 by a Zinc Ejection Mechanism. J BIOL CHEM , 284 (39) 26831 - 26838. 10.1074/jbc.M109.009498. Gold open access

Abstract

The hypoxic response in humans is regulated by the hypoxia-inducible 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-alpha 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-1 alpha 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.

Type:Article
Title:Epidithiodiketopiperazines Block the Interaction between Hypoxia-inducible Factor-1 alpha (HIF-1 alpha) and p300 by a Zinc Ejection Mechanism
Open access status:An open access publication
DOI:10.1074/jbc.M109.009498
Keywords:IONIZATION MASS-SPECTROMETRY, STRUCTURAL BASIS, METAL-COMPLEXES, IN-VIVO, GLIOTOXIN, TRANSCRIPTION, SPORIDESMIN, CELLS, INHIBITOR, PATHWAY
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutical and Biological Chemistry
UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry

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