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
  • 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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