Bisarylsulfonamides -novel small molecule inhibitors of p53-Mdm2 interaction

Abstract

The tumour suppressor p53 is at the centre of a network of regulatory pathways that guard over the continued integrity of the living cell and its progeny after exposure to different forms of stress, particularly those capable of inducing DNA damage. Tumour cells very frequently circumvent this control by disabling the function of p53 through mutation in p53 or one of its negative regulators, Mdm2. Modulation of the p53 -Mdm2 interaction has become a desirable approach for developing new anticancer therapeutics. Using a high through-put virtual screening program, LIDAEUSTM, and a structural model for the N-terminus of Mdm2, a novel class of small molecule inhibitors, thiophene-2-sulfonic acid phenylamides, potent antagonists of the p53-Mdm2 interaction, was discovered. Detailed structure-activity relationship information was obtained in a Mdm2/p53 fluorescence polarization competitive binding assay and the binding of bisarylsulfonamides to Mdm2 was confirmed by macromolecular NMR. The p53-Mdm2 antagonists induced significantly p53 transcriptional activity, measured in a luciferase-based p53 reporter gene assay. The p21Waf1/Cip1 gene product, which is transcriptionally regulated by p53, was induced in cancer cells treated with bisarylsulfonamides. The p53/Mdm2 antagonists potently and selectively killed cancer cells by apoptosis. The effects of the compounds was not limited to cells containing wild-type p53, suggesting that there is another target of Mdm2 that is affected by the interaction of bisarylsulfonamides with the N-terminus of Mdm2. Our results suggest that regulation of the E2F1 transcription factor is also involved in the mode of action of p53-Mdm2 antagonists, which is probably due to the known physical and functional interaction of Mdm2 with E2F1/DP1. The potential of these small molecule inhibitors of the p53-Mdm2 interaction as novel cancer therapeutics will be discussed.