Discovery Of A Novel Hdm2 Inhibitor With Potent In Vivo Anti-Tumor Activity

HDM2 is a major negative regulator of the p53 tumor suppressor pathway. Aberrant HDM2 overexpression and gene amplification contributed to accelerated cancer development and growth. Several small molecule inhibitors of HDM2-p53 protein-protein interaction have been reported in recent years with anti-tumor activities in tumor xenograft models. Here we describe a novel and potent small molecule inhibitor of HDM-p53 inhibitor that binds selectively to HDM2 with high affinity compared to HDM4. Treatment of cancer cells with this HDM2 inhibitor results in activation of p53 pathway as demonstrated by study of pharmacodynamic biomarkers both in cell culture and in tumor xenograft in vivo. More importantly, cancer cells response to this HDM2 inhibitor is mechanism based and dependent on the presence of functional p53 status as shown in a profiling of a broad-panel of cancer cell lines. This inhibitor is very potent against cancer cell growth with IC50 below 200 nM for most cell lines tested in vitro. It is orally bioavailable and has single agent activity that results tumor regression in SJSA-1 osteosarcoma model or growth inhibition in A549 NSCLC and A2780 ovarian cancer xenograft models. In addition, combination of this HDM2 inhibitor with various chemotherapy agents results in added or synergistic anti-tumor response both in vitro and in vivo in several human cancer xenograft models with limited bone marrow toxicity at the efficacious dose. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2785. doi:1538-7445.AM2012-2785