LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models

The human MET proto-oncogene encodes the MET kinase, also known as HGF receptor. HGF binds with high affinity to this trans-membrane tyrosine kinase receptor and is the only known ligand for this receptor. Binding of HGF to the extracellular domain of MET induces receptor multimerization, activates the intrinsic kinase activity of the receptor and results in the phosphorylation of multiple tyrosine residues in the intracellular region. The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis [ 1 ]. Dysregulated MET/HGF signaling leads to an abnormally activated cellular invasive program that plays a role in cellular transformation; epithelial-mesenchymsal transition; and tumor invasion, progression and metastasis. MET over-expression (with or without gene amplification), aberrant autocrine or paracrine ligand production, and missense MET mutations are mechanisms that lead to activation of the MET pathway in tumors and are associated with poor prognostic outcome [ 2 ]. Over-expression of MET, ligand-dependent activation, or MET amplification have also been implicated as potential mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibitor therapies [ 3 – 6 ]. Receptor cross-activation of other oncoproteins such as MST1R (also known as RON), AXL and PDGFRA by MET has also been reported [ 7 , 8 ]. We report the discovery and initial in vitro and in vivo evaluation of a small-molecule inhibitor LY2801653, whose development was initiated with the intent of targeting the MET kinase. We provide data to illustrate the in vitro effects of LY2801653 on the MET pathway-dependent cell scattering and cell proliferation, as well as its in vivo anti-tumor effects in mouse xenograft models. In subsequent nonclinical characterization, LY2801653 was screened against a larger panel of kinases and was found to have potent activity against several other receptor tyrosine oncokinases including MST1R (MET related tyrosine kinase), FLT3, AXL, MERTK, TEK, and ROS1, and against the serine/threonine kinases MKNK1/2. The potential value of MET and other inhibited targets within a number of malignancies is discussed. LY2801653 is currently in phase 1 clinical testing in patients with advanced cancer (trial I3O-MC-JSBA, NCT01285037).