Abstract 3613: Dual inhibitors against receptor tyrosine kinases c-Met and VEGFR-2 as efficacious antitumor agents in mouse xenograft tumor models

Vascular endothelial growth factor (VEGF) and the receptor VEGFR-2 (KDR) are the major components of angiogenesis signaling pathway and proven targets for the treatment of several solid tumors. However, recent studies have revealed that agents targeting VEGF/VEGFR-2 can promote tumor invasiveness and distant metastasis. These findings suggest that any future antiangiogenic therapies should be combined with mechanisms targeting cancer invasiveness and metastasis. Hepatocyte growth factor (HGF) receptor c-Met (HGFR) is a receptor tyrosine kinase considered critically involved in the control of cancer development, invasion, and metastasis. Studies have suggested that Inhibition of c-Met can not only reduce c-Met dependent tumor growth, but also decrease tumor invasion and metastasis. Thus, it is conceivable that targeting both c-Met and VEGFR-2 simultaneously will inhibit tumor growth and, at the same time, prevent tumor from invasion and metastasis through the following mechanisms: 1) synergy between VEGFR-2 and c-Met inhibition in antiangiogenesis; 2) inhibition of c-Met driven tumor growth; 3) disruption of c-Met mediated tumor invasion and metastasis. Compounds including ASP-08001 and 08126 were identified as small molecule, ATP competitive inhibitors of both c-Met and VEGFR-2 kinases through biochemical assays. In cellular studies, these compounds inhibited potently the activating phosphorylation of cytoplasmic domains of both kinases as well as c-Met and VEGFR-2 driven phenotypes such as cell proliferation, invasion, and angiogenesis. In addition, pharmacodynamic studies revealed that a single oral dose of a compound was able to inhibit the phosphorylation of cytoplasmic domains of both targeted and downstream kinases in tumor xenografts for up to 16 hours. The level of kinase inhibition in tumor tissues was well correlated with the plasma concentration of the compound inversely indicative of a proof of mechanism of actions. The antitumor efficacies of the compounds were demonstrated in xenograft tumor models of several human cancers including NSCLC, breast, gastric, and prostate cancers. Complete tumor growth arrest or even regression induced by oral dosing (50 or 100 mg/kg, q.d.) of the compounds was observed. Furthermore, pharmacokinetic studies suggested a promising drug-like PK profile for these compounds. Finally, single-dose acute toxicity studies of the compounds could not find a lethal dose in mice even though dosing had reached 5000mg/kg, suggesting a therapeutic index of greater than 50 and a promising safety profile. In summary, we reported here the discovery of small molecule, ATP-competitive, c-Met and VEGFR-2 inhibitors such as ASP-08001 and −08126 that have demonstrated strong potency in target inhibition and desired efficacies against a variety of human tumor models suggesting strong therapeutic potentials against human cancers. 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 3613.