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MET over-expression, 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. Scientists have developed a potent, orally bioavailable, inhibitor LY2801653 targeting MET kinase with promising anti-tumor activities in mouse xenograft models.

LY2801653 is a slow-off inhibitor of MET tyrosine kinase with a dissociation constant (Ki) of 2 nM and a pharmacodynamic residence time of 8.5 hours. The crystal structure of MET bound with LY2801653 indicates that LY2801653 is a type II ATP competitive inhibitor and illustrates that the mechanism of inhibition is through the stabilization of the inactive conformation. LY2801653 has also demonstrated in vitro effects on MET pathway-dependent cell scattering and cell proliferation, in vivo antitumor effects in MET amplified, MET autocrine and MET over-expressed xenograft models; and in vivo vessel normalization effects.

Furthermore, the binding of LY2801653 to MET appears to contribute 2 clinically intriguing features: the potential ability to retain potency versus a spectrum of mutations and the ability to sustain target inhibition due to its slow off-rate.

In the present study LY2801653 has been found to have potent activity against several other oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and MKNK1/2. In view of the reported transforming activity of these kinases, there may be clinical merit in evaluating LY2801653. In human bladder cancer, overexpression of MET/AXL/PDGFRA was shown to correlate with poor survival and contributed to the progression of human bladder cancer. ROS1 fusion proteins are found in glioblastoma, NSCLC and cholangiocarcinoma. MKNK1/2 are capable of regulating translation through the direct phosphorylation of eIF4E. Increased MKNK1/2-dependent phosphorylation of eIF4E is observed in head and neck squamous cell carcinoma and is correlated with a poor prognosis. Overexpression and activating mutations of DDR1/2 has been reported in sarcoma and in squamous cell lung cancer respectively.