Receptor tyrosine kinases (RTKs) are key regulators of a multitude of cell processes, including survival, proliferation, migration, invasion and angiogenesis. Aberrant activity of certain of these receptor tyrosine kinases has been associated with tumor progression in a wide variety of human malignancies, making them promising drug targets for cancer therapy. Although, in some instances, specific inhibition of just one of these RTKs suffices for inhibition of tumor progression, in the majority of cases, targeting more than one RTK could be required for therapeutic efficacy. These RTKs include MET, the receptor for hepatocyte growth factor (HGF), the fibroblast growth factor receptor, FGFR, and AXL. Dysregulation of MET activity, due to its overexpression or mutation, or overexpression of its ligand, has been consistently associated with aggressive phenotype, resistance to certain anti-cancer therapies and poor outcome. The FGFRs have a well-documented role in tumor angiogenesis, and, more recently, have been implicated directly in tumor cell survival, proliferation and metastasis in a wide range of tumor types. AXL is one of a family of three tyrosine kinase receptors (TAM family) involved in the pathogenesis of several human cancers and has also recently incited interest as a cancer therapeutic target.

S 49076 is a novel, potent, ATP-competitive tyrosine kinase inhibitor of MET, FGFR1/2/3 and AXL. S 49076 blocks autophosphorylation of these RTKs and their downstream signaling in cells with IC50 values of between 1 and 200 nM depending on the target and cell line. Furthermore, in kinase binding assays, S 49076 also binds to clinically-relevant MET mutated isoforms and a number of other kinases implicated in cancer pathology at concentrations of less than 100 nM. S 49076 is not, however, a potent inhibitor of VEGFR2. Although VEGFR2 is implicated in tumor angiogenesis, it also plays a major physiological role in the maintenance of vascular tone, and its inhibition by other RTK inhibitors has limited dosing of these molecules in the clinic. The unique inhibition profile of S 49076 may allow inhibition of oncogenic RTKs potentially without toxic effects encountered by VEGFR2 inhibitors.

In vitro, S 49076 inhibits the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocks MET-driven migration of lung carcinoma cells and inhibits colony formation of AXL-overexpressing hepatocarcinoma cells. In vivo, oral administration of S 49076 inhibits > 80% MET autophosphorylation in subcutaneous GTL-16 human gastric carcinoma tumors at 3 mg/kg. In both this GTL-16 model and in the MET-dependent U87-MG human glioblastoma model, S 49076 inhibits > 80% tumor growth at 6 mg/kg/day. S 49076 also inhibits FGFR2 autophosphorylation, downstream signaling and tumor growth in FGFR2-dependent SNU-16 gastric tumors, and tumor growth in LS-174T colon carcinoma.

Based on these preclinical studies showing a favorable and novel pharmacological profile and the potential of S 49076 as innovative anticancer agent, a phase I study is planned soon to evaluate an oral formulation of S 49076 in patients with advanced solid tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A238.