Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II)

被引：34

作者：

Jayatunga, Madura K. P. ^{[1
]}

Thompson, Sam ^{[1
]}

McKee, Tawnya C. ^{[2
]}

Chan, Mun Chiang ^{[1
]}

Reece, Kelie M. ^{[3
]}

Hardy, Adam P. ^{[1
]}

Sekirnik, Rok ^{[1
]}

Seden, Peter T. ^{[1
]}

Cook, Kristina M. ^{[3
]}

McMahon, James B. ^{[2
]}

Figg, William D. ^{[3
]}

Schofield, Christopher J. ^{[1
]}

Hamilton, Andrew D. ^{[1
]}

机构：

[1] Univ Oxford, Chem Res Lab, Dept Chem, Oxford OX1 3TA, England

[2] Ctr Canc Res, Mol Targets Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA

[3] NCI, Mol Pharmacol Sect, Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 94卷

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

Hypoxia; HIF; p300/CBP; Zinc ejection; Electrophile; Quinone; HYPOXIA-INDUCIBLE TRANSCRIPTION; ENDOTHELIAL GROWTH-FACTOR; SMALL-MOLECULE INHIBITOR; DNA-BINDING; FACTOR-I; FACTOR; 1-ALPHA; TUMOR-GROWTH; PROTEIN; HIF-1; HYDROQUINONE;

D O I：

10.1016/j.ejmech.2014.06.006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Protein-protein interactions between the hypoxia inducible factor (HIF) and the transcriptional coactivators p300/CBP are potential cancer targets due to their role in the hypoxic response. A natural product based screen led to the identification of indandione and benzoquinone derivatives that reduce the tight interaction between a HIF-1 alpha fragment and the CH1 domain of p300. The indandione derivatives were shown to fragment to give ninhydrin, which was identified as the active species. Both the naphthoquinones and ninhydrin were observed to induce Zn(II) ejection from p300 and the catalytic domain of the histone demethylase KDM4A. Together with previous reports on the effects of related compounds on HIF-1 alpha and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds. (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

页码：509 / 516

页数：8

共 42 条

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[42] 17BETA-ESTRADIOL-INDUCED UP-REGULATION OF TYPE II COLLAGEN EXPRESSION IS MEDIATED BY ER ALPHA/SP/SOX-9/P300 COMPLEX THROUGH COL2A1 PROMOTER/FIRST INTRON INTERACTIONS IN DIFFERENTIATED AND DEDIFFERENTIATED ARTICULAR CHONDROCYTES
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