Abstract 4534: A novel and potent small molecule antagonist of HDM2, SCH 1450206, activates the p53 pathway with mechanism-based activity

p53 is an attractive therapeutic target in oncology since aberrant regulation of p53 expression is associated with cancer development and progression. HDM2 is a primary negative regulator of p53 function in cells. The blockade of the p53-HDM2 interaction presents an attractive approach for development of drugs against tumors expressing wild-type p53. Here we report a novel and potent small molecule antagonist of HDM2, SCH 1450206. It binds selectively to the HDM2 protein with high affinity, with weak affinity to HDMX protein. SCH 1450206 induced dose- and time-dependent stabilization of p53 protein and its downstream targets in several human cancer cell lines with wild-type p53, but not in cell with p53 gene deletion. SCH 1450206-induced stabilization of p53 led to distinct changes in expression of p53 target genes regulating apoptosis and cell cycle checkpoints. Inhibition of cell proliferation and induction of apoptosis were surveyed in a panel of human tumor cell lines following SCH 1450206 treatment. Inactivation of p53 by shRNA in cell lines expressing wt-p53 abolished the inhibition of cell proliferation and appearance of senescence in response to SCH 1450206, suggesting the cellular activity of SCH 1450206 is p53 specific and mechanism-based. Taken together, our results demonstrated the mechanism of action of SCH 1450206, a novel HDM2 antagonist that can activate the p53 pathway, and offers a potential anti-tumor agent targeting tumors expressing wild-type p53. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4534.