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

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• Hypoxia-inducible factors (HIFs) are crucial transcription factors promoting tumor adaptation to hypoxic conditions.
• HIFs require cofactors p300 or CBP for transcriptional activation, making this interaction a target for cancer therapy.
• Previous studies indicated arylsulfonamides can inhibit HIF transcription and exhibit anticancer activity.

Purpose of the Study:

• To investigate the molecular mechanism by which KCN1 antagonizes HIF transcription.
• To determine if KCN1 interferes with the HIF-1α and p300/CBP cofactor interaction.
• To guide the synthesis of novel anticancer analogues based on KCN1's binding.

Main Methods:

• KCN1-bead affinity pull-down assays.
• (14)C-labeled KCN1 binding experiments.
• KCN1-surface plasmon resonance (SPR) measurements.
• Analysis of a previously reported NMR structure of the p300/HIF-1α complex.

Main Results:

• KCN1 directly binds to the CH1 domain of the p300 cofactor.
• This binding likely prevents the assembly of the p300/HIF-1α complex, inhibiting HIF transcriptional activity.
• Potential binding sites within the p300-CH1 domain were identified, enabling structure-guided analogue design.

Conclusions:

• KCN1 acts as an antagonist by disrupting the p300/HIF-1α interaction, offering a novel anticancer strategy.
• The identified binding mechanism and sites provide a foundation for developing potent HIF-targeting anticancer drugs.
• Further analogue synthesis is guided by the established two-site binding model and IC50 values.