1. Academic Validation
  2. Fluorescence polarization for the evaluation of small-molecule inhibitors of PCAF BRD/Tat-AcK50 association

Fluorescence polarization for the evaluation of small-molecule inhibitors of PCAF BRD/Tat-AcK50 association

  • ChemMedChem. 2014 May;9(5):928-31. doi: 10.1002/cmdc.201300499.
Ping Hu 1 Xinghui Wang Baiqun Zhang Shuai Zhang Qiang Wang Zhiyong Wang
Affiliations

Affiliation

  • 1 Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026 (P.R. China).
Abstract

A fluorescence polarization competitive assay was developed to efficiently screen and evaluate inhibitors of PCAF bromodomain/Tat-AcK50 protein-peptide interaction. A series of pyridine 1-oxide derivatives were synthesized and evaluated. Some of the novel compounds, 2-(3-aminopropylamino) pyridine 1-oxide derivatives, could be effective inhibitors of PCAF bromodomain/Tat-AcK50 association. Specifically, 2-(3-aminopropylamino)-5-(hydroxymethyl)pyridine 1-oxide hydrochloride (15) and the 5-((3-aminopropylamino)methyl) derivative (20) were found to be effective ligands for the PCAF BRD pocket. First preliminary cellular studies indicate that these small-molecule inhibitors have lower cytotoxicities and are potential leads for the anti-HIV/AIDS therapeutic strategy by targeting host-cell protein PCAF BRD to block HIV replication.

Keywords

HIV Tat; PCAF; fluorescence polarization; protein-peptide interactions; small-molecule inhibitors.

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