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[摘要]：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 HIP transcription in a bioassay, block the p300/HIF-1 alpha interaction, and exert potent anticancer activity in several animal models. In the present work, KCN1-bead affinity pull down, C-14-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-1 alpha assembly. Using a previously reported NMR structure of the p300/HIP-1 alpha 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. |
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