2. Academic Validation
  3. Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor

Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor

  • ACS Med Chem Lett. 2012 Jun 21;3(8):620-5. doi: 10.1021/ml300042k.
Qi Shi 1,  Shaoman Yin 2,  Stefan Kaluz 3,  Nanting Ni 4,  Narra Sarojini Devi 2,  Jiyoung Mun 5,  Danzhu Wang 4,  Krishna Damera 4,  Weixuan Chen 4,  Sarah Burroughs 4,  Suazette Reid Mooring 4,  Mark M Goodman 6,  Erwin G Van Meir 7,  Binghe Wang 4,  James P Snyder 8
Affiliations

Affiliations

  • 1 Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
  • 2 Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University School of Medicine , Atlanta, Georgia 30322, United States.
  • 3 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.
  • 4 Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University , Atlanta, Georgia 30302-4098, United States.
  • 5 Radiology and Imaging Sciences, Emory University , Atlanta, Georgia 30322, United States.
  • 6 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.
  • 7 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.
  • 8 Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States ; Emory Institute for Drug Discovery, Emory University , Atlanta, Georgia 30322, United States.
PMID: 24936238 DOI: 10.1021/ml300042k
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.

Keywords

HIF arylsulfonamide inhibitors; KCN1; QSAR; binding model; hypoxia; p300; solid tumors.

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