Binding model for the interaction of anticancer arylsulfonamides with the p300 transcription cofactor

Academic Article


  • 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, 14C-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 IC 50 values has allowed establishment of a modest ROC-based enrichment and creation of a guide for future analogue synthesis. © 2012 American Chemical Society.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Shi Q; Yin S; Kaluz S; Ni N; Devi NS; Mun J; Wang D; Damera K; Chen W; Burroughs S
  • Start Page

  • 620
  • End Page

  • 625
  • Volume

  • 3
  • Issue

  • 8