c-Met inhibitor

Many c-Met inhibitors are currently in clinical trials. Crizotinib and Cabozantinib were the first to be approved by the U.S. FDA; Crizotinib received accelerated approval for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by a test approved by the U.S. Food and Drug Administration (FDA). Cabozantinib was approved in November 2012 for the treatment of medullary thyroid cancer and it has also started clinical trials for the treatment of prostate, bladder, ovarian, brain, melanoma, breast, non-small cell lung, pancreatic, hepatocellular and kidney cancers. c-Met stimulates cell scattering, invasion, protection from apoptosis and angiogenesis. c-Met is a receptor tyrosine kinase, which can cause a wide variety of different cancers, such as renal, gastric and small cell lung carcinomas, central nervous system tumours, as well as several sarcomas when its activity is dysregulated. Targeting the ATP binding site of c-Met by small molecules inhibitors is one strategy for inhibition of the tyrosine kinase. Early in the 1980s MET was described as the protein product of a transforming oncogene. Initial attempts to identify ATP-competitive c-Met inhibitors in 2002 led to the discovery of K252a, a staurosporine-like inhibitor which blocks c-Met.K252a was the first structure to be solved in complex with the unphosphorylated MET kinase domain. It forms two hydrogen bonds between the hinge and pyrralocarbazole subunit. Later, series of more selective c-Met inhibitors were designed, where an indolin-2-one core (encircled in figure 1) was present in several kinase inhibitors. SU-11274 was evolved by substitution at the 5-position of the indolinone and by adding a 3,5-dimethyl pyrrole group, PHA-665752 was evolved – a second-generation inhibitor with better potency and activity. Interest in this field has risen rapidly since 2007 and over 70 patent applications had been published in mid-2009. Intensive efforts have been exerted in the pharmaceutical industry following the acceptance of c-Met as a suitable target for cancer therapy. 20 crystal structures with and without ligands have been published and in 2010 nearly a dozen small molecule c-Met inhibitors have been tested clinically. Receptor tyrosine kinases (RTKs) are a vital element in regulating many intracellular signal transduction pathways.Met tyrosine kinase is the receptor for hepatocyte growth factor (HGF), also known as scatter factor (SF). HGF is mostly expressed on epithelial cells and mesenchymal cells, for example smooth muscle cells and fibroblasts). HGF is normally active in wound healing, liver regeneration, embryo and normal mammalian development, organ morphogenesis.