c-Met/HGFR

c-Met/HGFR

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.

 Chemical-structures-of-some-c-Met-inhibitors-Crizotinib-Cabozantinib-Foretinib-Tivantinib-and-LY-2801653

 

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.

BOC Sciences can provide many c-Met inhibitors with high quality. BOC Sciences is equipped with advanced equipment and professional responsible staffs are available for your service. For more detail information and more customized solution, please do not hesitate to contact us. We are ready for your service all the time.

References:

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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