page_title: C-Met inhibitor
section_title: History
hierarchical_section_title: C-Met inhibitor / History
caption_attribution_description: English: K252 binding to c-met
context_page_description: c-Met inhibitors are a class of small molecules that inhibit the enzymatic activity of the c-Met tyrosine kinase, the receptor of hepatocyte growth factor/scatter factor. These inhibitors may have therapeutic application in the treatment of various types of cancers.
  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 in 2011 for the treatment of patients with locally advanced or metastatic non-small cell lung cancer, while cabozantinib was approved in 2012 for the treatment of medullary thyroid cancer and it has also started clinical trials for the treatment of several other types of cancer.
  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.
context_section_description: 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.
caption: Figure 3. K252a, the first small molecule Met inhibitor to be solved in complex with the unphosphorylated Met kinase domain. Two key hydrogen bonds form between the hinge of Met and the pyrralocarbazole.[8]
exif: {}