c-MET INHIBITORS IN CANCER TREATMENT

by Selleckchem | Aug 20 2012

c-MET AND ITS INHIBITION:
c-Met is encoded by a proto-oncogene and is also known as HGF-R or hepatocyte growth factor receptor. As it is a proto-oncogene, therefore, its hyperactivation is involved in development of different cancers. c-Met is known to form new blood vessels in growing tumors and hence help their invasion to other tissues. Different examples of cancers involving c-Met aberrant behavior are stomach cancer, liver cancer, breast cancer, thyroid cancer, ovarian cancer and brain cancer. Because of involvement of this particular oncoprotein in many cancers, it has remained target in lots of research related to anti-cancer therapy [1]. Lots of c-Met antagonists have been developed and one of the examples is c-Met inhibitors that has been implicated clinically and therapeutically [2]. Different other antagonists and agonists of c-Met are also being used in order to get an understanding about different functions of c-Met and the types of interactions that it has with other molecules in the signaling cascade. Many of the c-Met inhibitors are commercially available at reasonable prices for example tyrosine kinase inhibitor. These inhibitors can be easily bought from the suppliers for any purpose.

DIFFERENT TYPES OF c-MET INHIBITORS:
Many different types of c-Met inhibitors are there and most of them are still in development process. One of the examples c-Met inhibitors is ARQ 197. It is a small molecule that is non-competitive in its action and suppresses tumor growth by inhibiting c-Met Receptor Tyrosine Kinases. MK-2461 is also a famous and potent inhibitor of c-Met. It is also very specific for RTKs in c-Met signaling pathway and inhibits phosphorylated RTK. SU11274 another c-Met inhibiting molecule that targets c-Met in its mutant forms [3]. PHA665752 is characterized by and has been seen to affect phosphorylation process of the protein that is HGF dependent. Some types of amplifications of c-Met in cancer, make it more susceptible to the drug i.e., PHA665752 [4]. The above mentioned examples are c-Met specific while there are some of the inhibitors that have multiple type of actions on different molecules of signaling cascade. Foretinib is one of the examples that in addition to inhibiting c-Met, can also inhibit different Receptor tyrosine kinases for example KDR or VEGFR2. K252 is a c-Met specific inhibitor that has shown reduction in oncogenesis process [5].

c-MET INHIBITORS IN CLINICS:
Several preclinical and clinical trials were made in order to unveil the inhibitory activity of different types of c-Met inhibitors. Several of these inhibitors showed potency during preclinical trials but remained inactive in clinical studies. c-Met is constitutively expressed in cancerous cells and ARQ 197 when used in these cell lines showed induction of apoptosis by activation of pathway involving caspases. Tumor growth got inhibited in different mouse models of xenografts at the oral administration of ARQ 197. Due to these results the inhibitor was brought into clinical trials and was studied in phase II for different cancers [6]. One of the examples of strong inhibitors is PHA665752 that has shown efficiency in c-Met transformed cells with TPR induction, biologically and biochemically. It has been effectively used singly against Non small cell lung cancer and also showed synergistic effects when used with FRAP1 inhibitor i.e., Rapamycin [7]. These successful trials encourage the scientists to further use and experiment with these inhibitors in clinical trials.

REFERENCES:
1. Ma PC, e.a., c-Met: Structure, functions and potential for therapeutic inhibition Cancer and Metastasis Reviews, 2003.
2. Eder JP, e.a., Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer. Clin Cancer Res, 2009.
3. Berthou S, e.a., The Met kinase inhibitor SU11274 exhibits a selective inhibition pattern toward different receptor mutated variants. Oncogene, 2004.
4. Smolen GA, e.a., Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc. Natl. Acad. Sci. U.S.A., 2006.
5. Morotti A, e.a., K252a inhibits the oncogenic properties of Met, the HGF receptor. Oncogene, 2002.
6. Munshi N, e.a., ARQ 197, a novel and selective inhibitor of the human c-Met receptor tyrosine kinase with antitumor activity. Mol Cancer Ther., 2010.
7. Ma PC, e.a., A Selective Small Molecule c-Met Inhibitor, PHA665752, Cooperates with Rapamycin. Clin Cancer Res, 2005

Cat.No.	Product Name	Information
S2753	Tivantinib	Tivantinib is the first non-ATP-competitive c-Met inhibitor with K_i of 0.355 μM in a cell-free assay, little activity to Ron, and no inhibition to EGFR, InsR, PDGFRα or FGFR1/4. Tivantinib (ARQ 197) induces a G2/M arrest and apoptosis.
S2774	MK-2461	MK-2461 is a potent, multi-targeted inhibitor for c-Met(WT/mutants) with IC50 of 0.4-2.5 nM, less potent to Ron, Flt1; 8- to 30-fold greater selectivity of c-Met targets versus FGFR1, FGFR2, FGFR3, PDGFRβ, KDR, Flt3, Flt4, TrkA, and TrkB. Phase 1/2.
S1080	SU11274	SU11274 (PKI-SU11274) is a selective Met (c-Met) inhibitor with IC50 of 10 nM in cell-free assays, no effects on PGDFRβ, EGFR or Tie2. SU11274 induces autophagy, apoptosis and cell cycle arrest.
S1070	PHA-665752	PHA-665752 is a potent, selective and ATP-competitive c-Met inhibitor with IC50 of 9 nM in cell-free assays, >50-fold selectivity for c-Met than RTKs or STKs.
S1111	Foretinib	Foretinib is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met (c-Met) and KDR with IC50 of 0.4 nM and 0.9 nM in cell-free assays. Less potent against Ron, Flt-1/3/4, Kit (c-Kit), PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.
S1039	Rapamycin	Rapamycin is a specific mTOR inhibitor with IC50 of ~0.1 nM in HEK293 cells.Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1. Rapamycin is an autophagy activator and an immunosuppressant.