Abstract 4533: In vivo activation of the p53 pathway leading to tumor regression by a novel and potent HDM2 antagonist SCH 1450206

The HDM2-p53 protein-protein interaction is well characterized through X-ray crystallography. Disrupting this HDM2-p53 protein-protein interaction by a small molecule would therefore release the p53 from the negative inhibition of HDM2 and restore its anti-tumor activities. Peptides, antisense oligonucleotides and small molecules have been identified which disrupt this interaction and result in the stabilization of p53 protein and activation of its downstream targets. We have recently discovered a novel, potent HDM2 antagonist (SCH 1450206) with mechanism-based activity both in vitro and in vivo. Oral administration of SCH 1450206 as a single agent resulted in tumor regression in the SJSA-1 osteosarcoma xenograft model without any observable toxicity. Analysis of the pharmacodynamic markers demonstrated that the anti-tumor activity of SCH 1450206 correlated with the robust activation of p53 pathway in vivo. In addition to its single agent anti-tumor activity, combination of HDM2 antagonist SCH 1450206 with various cytotoxics resulted in further tumor growth inhibition in various human cancer xenograft models. The activation of p53 pathway in vivo targets preferentially to tumor tissues compared to high proliferating and radio sensitive organs of the mouse at the efficacious dose. The lack of single agent toxicity at the efficacious dose and schedule would potentially allow the combination of this type of HDM2 antagonist with other anti-cancer agents at full dose in the clinic. 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 4533.