Abstract 4437: Preclinical characterization of AMG 900, an orally available small molecule inhibitor of aurora kinases in phase 1 clinical trials

Abstract

Abstract Background: The aurora family of serine-threonine kinases (aurora-A, -B, -C) regulate cell-cycle progression in mammalian cells. Aurora-A and aurora-B are essential for proper chromosome congression, segregation, and cytokinesis during mitosis, whereas aurora-C function appears restricted to male meiosis. Aurora-B is responsible for the direct phosphorylation of histone H3 on serine-10. Aurora-A and aurora-B expression is elevated in a variety of human cancers and is associated with advanced clinical staging and poor prognosis. The emergence of aurora kinases as key mitotic regulators and their potential role in tumorigenesis has focused substantial interest in developing selective small molecule inhibitors for the treatment of human cancers. Objective: The aim of this study was to determine the in vitro effects of AMG 900 on a panel of tumor cell lines and profiling its antitumor activity across multiple human xenograft models. Results: AMG 900 is a novel ATP competitive small molecule inhibitor that is potent and highly selective for aurora kinases A, B, and C. In cells, AMG 900 inhibits autophosphorylation of aurora-A and aurora-B as well as the phosphorylation of histone H3. The predominant cellular response of tumor cells to AMG 900 treatment is aborted cell division, which leads to endoreduplication and cell death. The effect of AMG 900 was tested in a panel of 26 cell lines to evaluate its potential to inhibit cell proliferation across multiple tumor types. AMG 900 inhibited the proliferation of tumor cell lines at low nanomolar concentrations (EC50 values 1-6 nM), including a number of multidrug resistant (MDR) cell lines expressing ATP-binding cassette transporters (P-gp and BCRP1). In contrast, paclitaxel and three aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358) showed a loss of potency in these MDR cell lines compared to matched parental cell lines. In nude mice, oral administration of AMG 900 inhibited phosphorylation of histone H3 in tumors in a concentration- and dose-dependent manner. The effect of AMG 900 was tested in a panel of nine human xenografts representing five tumor types (breast, colon, lung, pancreatic, and uterine). Oral administration of AMG 900 at 15 mg/kg BID for two consecutive days per week or 3 mg/kg BID every day inhibited tumor growth (50-97%, P < 0.005) in all nine of the xenograft models. Importantly, three of these xenograft models are resistant to taxanes. Mice treated with efficacious doses of AMG 900 showed a transient loss of body weight and bone marrow cellularity, consistent with its on-mechanism effects on normal proliferating cells. Conclusion: Based on these preclinical activities, AMG 900 has the potential to treat advanced cancers, including tumors resistant to chemotherapeutic agents such as paclitaxel and docetaxel. AMG 900 is currently undergoing phase 1 clinical evaluation in patients with advanced solid tumors. 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 4437.