In response to cellular stress, the p53 tumor suppressor is activated to modulate cell cycle progression, DNA repair, and cell death. The activity of p53 is tightly regulated by MDM2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation. Inhibition of the MDM2-p53 interaction in tumors carrying wild-type p53 can therefore reactivate p53 and elicit an anti-cancer effect. Small molecule inhibitors of the MDM2-p53 interaction remains a promising strategy for cancer therapy and a number of these compounds are in clinical development.
An isoindolinone series, identified by the Northern Institute for Cancer Research (NICR), has been used as a starting point for the development of potent MDM2-p53 inhibitors. Structure based drug design was applied during lead optimisation to gain potency whilst also focusing on stabilizing the main metabolically labile position and reducing lipophilicity. This approach led to potent compounds with EC50 <1 nM against MDM2 in cell-free ELISA assays and EC50 <30 nM for p53 induction in SJSA-1 osteosarcoma cells. Further analyses of the compounds demonstrated an increase in the levels of p53 and p53 transcriptional targets as a result of inhibiting the MDM2-p53 interaction. Using three pairs of isogenic cell lines, the compounds were shown to be specific for cell lines with wild-type p53. Key compounds were also characterized in pharmacokinetic and pharmacodynamic studies in mice bearing the SJSA-1 tumor xenograft where they displayed strong induction of p53, 3 hours post oral administration, together with an increase in the expression of p53 target genes p21 and MDM2. These potent MDM2-p53 inhibitors have also shown significant in vivo efficacy in the SJSA-1 xenograft model at well tolerated oral doses. Thus, promising lead compounds were identified, meriting further optimization of the series.
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Development of a potent class of small molecule inhibitors of the MDM2-p53 protein-protein interaction