title: Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor.
abstract: Hypoxia inducible factors (HIFs) are transcription factors that activate expression of multiple gene products and promote tumor adaptation to a hypoxic environment. To become transcriptionally active, HIFs associate with cofactors p300 or CBP. Previously, we found that arylsulfonamides can antagonize HIF transcription in a bioassay, block the p300/HIF-1α interaction, and exert potent anticancer activity in several animal models. In the present work, KCN1-bead affinity pull down, (14)C-labeled KCN1 binding, and KCN1-surface plasmon resonance measurements provide initial support for a mechanism in which KCN1 can bind to the CH1 domain of p300 and likely prevent the p300/HIF-1α assembly. Using a previously reported NMR structure of the p300/HIF-1α complex, we have identified potential binding sites in the p300-CH1 domain. A two-site binding model coupled with IC50 values has allowed establishment of a modest ROC-based enrichment and creation of a guide for future analogue synthesis.
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University School of Medicine , Atlanta, Georgia 30322, United States.
authors.forename: Shaoman
authors.initials: S
authors.lastname: Yin
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University School of Medicine , Atlanta, Georgia 30322, United States ; Winship Cancer Institute, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kaluz
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30302-4098, United States.
authors.forename: Nanting
authors.initials: N
authors.lastname: Ni
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University School of Medicine , Atlanta, Georgia 30322, United States.
authors.forename: Narra Sarojini
authors.initials: NS
authors.lastname: Devi
authors.affiliation: Radiology and Imaging Sciences, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Mun
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30302-4098, United States.
authors.forename: Danzhu
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30302-4098, United States.
authors.forename: Krishna
authors.initials: K
authors.lastname: Damera
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30302-4098, United States.
authors.forename: Weixuan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30302-4098, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Burroughs
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30302-4098, United States.
authors.forename: Suazette Reid
authors.initials: SR
authors.lastname: Mooring
authors.affiliation: Radiology and Imaging Sciences, Emory University , Atlanta, Georgia 30322, United States ; Winship Cancer Institute, Emory University , Atlanta, Georgia 30322, United States ; Department of Hematology and Medical Oncology, Emory University School of Medicine , Atlanta, Georgia 30322, United States.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University School of Medicine , Atlanta, Georgia 30322, United States ; Department of Hematology and Medical Oncology, Emory University School of Medicine , Atlanta, Georgia 30322, United States ; Winship Cancer Institute, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30302-4098, United States.
authors.forename: Binghe
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States ; Emory Institute for Drug Discovery, Emory University , Atlanta, Georgia 30322, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
keywords: HIF arylsulfonamide inhibitors; KCN1; QSAR; binding model; hypoxia; p300; solid tumors