Abstract
Activation of p53 by blocking the interaction of MDM2-p53 using non-peptide small-molecule inhibitors is being pursued as a promising new cancer therapeutic strategy. Although genetic ...activation of p53 has been shown to achieve complete tumor eradication in mice, the best small-molecule inhibitors of the MDM2-p53 interaction reported to date (Nutlins including RG7112 or first generation spiro-oxindoles such as AT219) can only inhibit tumor growth but fail to achieve significant tumor regression in animal models of human cancer. In the present study, we demonstrate, for the first time, that 2 highly optimized spiro-oxindole compounds, Compound A and Compound B, are capable of achieving complete tumor regression or even permanent cure in multiple xenograft models of human cancer (sarcoma, leukemia, prostate) without causing any significant signs of toxicity to animals. They bind to human MDM2 protein with Ki values of <1 nM, 5000-times more potent than the wild-type p53 peptide. These potent MDM2 inhibitors are capable of activating p53 at concentrations as low as 30–100 nM and induce robust p53-dependent cell cycle arrest and apoptosis against tumor cells with wild-type p53. Both compounds display good pharmacokinetic and pharmacodynamic profiles in animals. For instance, clearance is low in mice and moderate in dog representing 4 and 15 % of hepatic blood flow respectively. Importantly, excellent oral bioavailability was shown with 25–60 % F in dogs and 75 % F in mice and both compounds trigger rapid and sustained activation of pharmacodynamic biomarkers such as p53, p21, MDM2 and PUMA. Molecular profiling using large number of primary AML leukemia samples have identified that AML cells with wild-type p53 and FLT3-ITD mutation are exquisitely sensitive to apoptosis induction by our MDM2 inhibitors, suggesting an interesting clinical trial rationale. Toxicology studies are ongoing.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-204. doi:10.1158/1538-7445.AM2011-LB-204
