Discovery of niclosamide as a p300/transcription factor protein–protein interaction inhibitor

Abstract

Protein-protein interactions (PPIs) are crucial in various biological processes and are attractive targets for drug discovery. In this study, we identified niclosamide (9) as a novel inhibitor of the hypoxia-inducible factor 1α (HIF-1α)/p300 PPI from the RIKEN NPDepo compound library using a fluorescence anisotropy-based screening method. We synthesized niclosamide azide (10) as a photoaffinity labelling probe to identify the p300 binding site of compound 9 and elucidated the binding mode using photoaffinity labelling experiments and molecular docking simulations. Furthermore, we demonstrated that compound 9 inhibited not only HIF-1α/p300 PPI but also p300-transcription factor PPIs, including interaction with p53 and STAT3, thereby suppressing the expression of BAX and c-MYC, respectively.