c-Met, also called tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR), is a protein that in humans is encoded by the MET gene. The protein possesses tyrosine kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor.

c-Met is a highly binding receptor tyrosine kinase that belongs to the RON subfamily and is the only known receptor for the scattering factor or hepatocyte growth factor (HGF). c-Met is encoded by the oncogene Met gene. c-Met protein is a heterodimer linked by a disulfide bond between the 50 kD α chain and the 145 kD β chain. It is divided into an extracellular domain and an intracellular domain. Its extracellular domain contains three functionally distinct domains: the N-terminal ligand binding domain covering the entire α chain and part of the β chain (SEMA region), a small cystine rich region with four conserved disulfide bonds, and immunity Immunoglobulin-like domain. Its intracellular domain also consists of three regulatory regions: the near-membrane domain with Tyr1003 phosphorylation sites, the tyrosine kinase catalytic domain with Tyr1234 and Tyr1235 phosphorylation sites, and C-terminal multifunctional binding region with Tyr1349 and Tyr1356 bound to tyrosine.

c-Met is an important target for anti-tumor therapy. c-Met is abnormally expressed in a variety of malignant tumors, regulates the growth, invasion, metastasis, and apoptosis of tumor cells. After binding to the extracellular domain of c-Met, HGF induces the phosphorylation of c-Met and recruits a variety of intercellular cytokines in the C-terminal multifunctional domain, such as growth factor receptor binding protein-1 (GAB1), growth factor receptor binding protein-2 (GAB2), etc. RAS/MAPK, PI3K/AKT, JAK/STAT pathways are then activated. This regulates cell growth, migration, proliferation, and survival. Abnormalities in the c-Met pathway induce tumorigenesis and metastasis, and abnormally high levels of c-Met are found in a variety of human malignancies such as bladder, gastric, lung, and breast cancers. In addition, c-Met is also associated with tumor resistance to multiple kinase inhibitors. The interaction between c-Met and various membrane receptors (cross-talk) constitutes a complex network system. The interactions between c-Met and these membrane receptors promote tumorigenesis and metastasis and induce drug resistance.

At present, there are two types of anti-tumor drugs for the c-Met pathway: one is a monoclonal antibody against HGF or c-Met; the other is a small molecule inhibitor against c-Met. According to the chemical structure of the inhibitors and the crystal binding pattern to c-Met, c-Met small molecule inhibitors are divided into two categories. Class I c-Met inhibitors in the kinase pocket bind to c-Met as a U-shaped conformation surrounding by Met1121 and binding in the hinge region. Class I inhibitors are highly selective for c-Met. Class II c-Met inhibitors are more stretchier and the binding region extends from the ATP site to Ile1145 near the C-C helix. Most Class II inhibitors are non-specific inhibitors that have inhibitory effects on multiple kinase targets and are superior to Class I inhibitors. So far, the small molecular inhibitors have been approved by the FDA for listing. Some small molecule c-Met inhibitors are in clinical research, such as , and LY-2801653. Their chemical structures are shown in Fig.1.



Fig. 1. Chemical structures of some c-Met inhibitors: Crizotinib, Cabozantinib, Foretinib, Tivantinib, and LY-2801653.


Crizotinib (PF-02341066) is a class I c-Met inhibitor and has an inhibitory effect on c-Met, ALK, etc. The IC50 is 11, 24 nmol/L. In 2013, FAD approved the use of crizotinib for the treatment of lymphoma kinase-positive advanced and metastatic non-small cell lung cancer. Abnormal HGF secretion and activation of c-Met were found in leukemia cells treated with the c-Met inhibitor Crizotinib. Due to the compensatory up-regulation of HGF secretion, the c-Met pathway was partially restored, resulting in drug resistance in a short period of time. Cabozantinib inhibits phosphorylation of c-Met and VEGFR-2 in an in vivo tumor model, demonstrating potent antitumor metastasis and anti-angiogenic activity in preclinical models. Compared with inhibitors that acted on VEGFR signaling alone, no increase in lung tumor burden was found in the Cabozantinib-treated tumor metastasis model. Cabozantinib is a potent inhibitor of tumor angiogenesis and metastasis in patients with tumors with deregulated c-Met and VEGFR signaling pathways. In 2012, FDA approved the marketing of cabozantinib (Cometriq) for the treatment of medullary thyroid cancer.

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1. Cui, J.J., (2014) Targeting receptor tyrosine kinase MET in cancer: small molecule inhibitors and clinical progress. J Med Chem. 57 (11): 4427-4453.

2. Maroun, C.R., Rowlands, T., (2014) The Met receptor tyrosine kinase: a key player in oncogenesis and drug resistance. Pharmacol Ther. 142 (3): 316-338.

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