NVP-TAE226, a potent dual FAK/IGF-IR kinase inhibitor, prevents breast cancer metastasis in vivo

Abstract

13163 Background: Focal Adhesion Kinase (FAK) and Insulin-like Growth Factor-1 Receptor (IGF-IR) kinase are attractive anti-cancer drug targets because they are both drivers of tumor cell proliferation, migration, and survival. Although virtually every cell type expresses FAK, it is generally overexpressed in tumor cells. FAK levels are greatest in highly metastatic tumors. A selective FAK inhibitor would be expected to halt or kill invasive tumor cells, and potentially interfere with normal cell migration (e.g. endothelial cells). IGF-IR function is required for tumor cell survival, but dispensable for survival of normal cells. Therefore, a dual inhibitor of both kinases may selectively block the growth, migration, and survival of FAK- and IGF-IR- expressing tumor cells compared to proliferating and migrating normal cells. Methods: NVP-TAE226, a novel small molecule developed as an inhibitor of FAK, was evaluated in kinase enzymatic assays, cell-based kinase assays and 4T1 metastatic breast carcinoma in vivo model. Results: NVP-TAE226 inhibits FAK with low nanomolar IC 50 values in a purified kinase enzymatic assay. In cell-based kinase assays, FAK and IGF-IR kinase were inhibited with an IC 50 range of 100 to 300 nM compared to the other kinases tested which were >10-fold less sensitive. Oral administration of NVP-TAE226 inhibited 4T1 murine breast tumor growth and metastasis to the lung in a dose-dependent manner. The compound was well tolerated in mice as determined by measuring changes in body weight. The highest dose of 100 mg/kg, qd, 5x/week showed T/C value of 18%. Inhibition of FAK autophosphorylation at Y397 and Akt phosphorylation at Serine473 was observed in a dose-dependent manner in 4T1 breast carcinoma. Conclusions: NVP-TAE226 represents a novel class of selective and small molecule kinase inhibitors that have potential clinical applications with a potent in vivo activity. [Table: see text]