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 (HGF/SF). 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.
History
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.
Introduction
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.
c-Met dysregulation can be due to overexpression, gene amplification, mutation, a ligand-dependent auto- or paracrine loop or an untimely activation of RTK. All these factors affect the survival of cells, their proliferation and motility. They also lead to cancers and resistance to therapies which aim to treat them. Patients with aberrant c-Met activity usually have a poor prognosis, aggressive disease, increased metastasis and shortened survival. This is why targeting the HGF/c-MET signalling pathway has been untaken as a treatment for cancer, and several different therapeutic approaches are being clinically tested. A variety of approaches have been used to target c-Met, each focusing on one of the serial steps that regulate c-Met activation by antibodies, peptide agonists, decoy receptors and other biologic inhibitors or small molecules inhibitors.
Structure and function
The c-Met RTK subfamily is different in structure to many other RTK families: The mature form has an extracellular α-chain (50kDa) and a transmembrane β-chain (140kDa) that are linked together by a disulfide bond. The beta chain contains the intracellular tyrosine kinase domain and a tail on the C-terminal which is vital for the docking of substrates and downstream signalling.
HGF is the natural high-affinity ligand for Met. Its N-terminal region binds to Met and receptor dimerization as well as autophosphorylation of two tyrosines occur in the activation loop (A-loop) in the kinase domain of Met.
Phosphorylation occurs in tyrosines close to the C-terminus, creating a multi-functional docking site which recruits adaptor proteins and leads to downstream signalling. The signaling is mediated by Ras/Mapk, PI3K/Akt, c-Src and STAT3/5 and include cell proliferation, reduced apoptosis, altered cytoskeletal function and more.