1,4-benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction: discovery and SAR

A library of 1,4-benzodiazepine-2,5 -diones was screened for binding to the p53-binding domain of HDM2 using Thermofluor(R), a miniaturized thermal denaturation assay. The hits obtained were shown to bind to HDM2 in the p53-binding pocket using a fluorescence polarization (FP) peptide displacement assay. The potency of the series was optimized, leading to sub-micromolar antagonists of the p53-HDM2 interaction. (C) 2004 Elsevier Ltd. All rights reserved.