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

• Published in: European journal of medicinal chemistry 2015-04, Vol.94, p.509-516
• Main Authors: Jayatunga, Madura K.P., Thompson, Sam, McKee, Tawnya C., Chan, Mun Chiang, Reece, Kelie M., Hardy, Adam P., Sekirnik, Rok, Seden, Peter T., Cook, Kristina M., McMahon, James B., Figg, William D., Schofield, Christopher J., Hamilton, Andrew D.
• Format: Article
• Language: English
• Subjects: Dose-Response Relationship, Drug; E1A-Associated p300 Protein - metabolism; Electrophile; HIF; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Indans - chemistry; Indans - pharmacology; Models, Molecular; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; p300/CBP; Protein Binding - drug effects; Quinone; Quinones - chemistry; Quinones - pharmacology; Structure-Activity Relationship; Zinc - chemistry; Zinc - pharmacology; Zinc ejection
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.06.006

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-1α 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-1α and other systems, the results suggest that care should be taken in interpreting biological results obtained with highly electrophilic/thiol modifying compounds. [Display omitted]