title: Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II).
abstract: 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.
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom.
authors.forename: Madura K P
authors.initials: MK
authors.lastname: Jayatunga
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom. Electronic address: sam.thompson@chem.ox.ac.uk.
authors.forename: Sam
authors.initials: S
authors.lastname: Thompson
authors.affiliation: Center for Cancer Research, Molecular Targets Laboratory, Frederick National Laboratory Cancer Research, Frederick, MD 21702, USA.
authors.forename: Tawnya C
authors.initials: TC
authors.lastname: McKee
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom.
authors.forename: Mun Chiang
authors.initials: MC
authors.lastname: Chan
authors.affiliation: NCI, Mol. Pharmacol. Sect., Med. Oncol. Branch, Ctr. Canc. Res., NIH, Bldg. 10, Room 5A01, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Kelie M
authors.initials: KM
authors.lastname: Reece
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Hardy
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom.
authors.forename: Rok
authors.initials: R
authors.lastname: Sekirnik
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Seden
authors.affiliation: NCI, Mol. Pharmacol. Sect., Med. Oncol. Branch, Ctr. Canc. Res., NIH, Bldg. 10, Room 5A01, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Cook
authors.affiliation: Center for Cancer Research, Molecular Targets Laboratory, Frederick National Laboratory Cancer Research, Frederick, MD 21702, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: McMahon
authors.affiliation: NCI, Mol. Pharmacol. Sect., Med. Oncol. Branch, Ctr. Canc. Res., NIH, Bldg. 10, Room 5A01, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: figgw@helix.nih.gov.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom. Electronic address: andrew.hamilton@admin.ox.ac.uk.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D004305:Dose-Response Relationship, Drug; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007189:Indans; D009942:Organometallic Compounds; D011809:Quinones; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D015032:Zinc
keywords: Electrophile; HIF; Hypoxia; Quinone; Zinc ejection; p300/CBP