CANCER TREATMENT BY c-MET INHIBITORS

by Selleckchem | Aug 26 2012

c-MET INHIBITION: APPLICATIONS IN CANCERS:
A proto-oncogene encoding the hepatocyte growth factor receptor or HGF-R is known as c-Met, and its hyperactivation causes certain changes like angiogenesis or formation of the new blood vessels leading to the invasive growth of tumor. The aberrant regulation of Met has reported to the leading cause of many types of cancer like liver cancer, stomach cancer, breast cancer, ovarian cancer, thyroid cancer and brain cancers. Due to this particular property of c-Met gene, its inhibition process has become an attractive target for the therapeutic use [1]. That’s why huge research is being made for the synthesis of antagonist of c-Met or simply am7 inhibitor having clinical and therapeutic implications [2]. Along with this application, the c-Met agonists and antagonists are being utilized for understanding of different cellular cascades and throwing light on interactions of c-Met with other molecules. Many of these commercial c-Met inhibitors like bayer kinase inhibitors are easily available from their suppliers and one has an easy access to them.

c-MET INHIBITORS:
Various c-Met inhibitors related to c-Met cascade are under development process. ARQ 197 is an inhibitor specific for c-Met pathway and is a small non-competitive molecule which exhibits tumor suppressing property by adopting the selective inhibition of c-Met RTK (receptor tyrosine kinase). MK-2461 is another potent and famous c-Met inhibitor specific in nature and targets the RTK in its phosphorylated form. SU11274 is another inhibitor molecule that targets different mutant forms of Met [3]. PHA665752 is also a small c-Met inhibitor that is characterized and observed to affect the HGF-dependent process of phosphorylation. It was also found that some specific amplifications of Met used to make the cancers and tumors more susceptible to therapy by PHA-665752 [4]. The above are the specific c-Met inhibitors but there some multiple molecules as well having the property of inhibition even at a wider range of spectrum. For example Foretinib is an inhibitor molecule that is found to check the functions of different RTKs for instance VEGFR2 or KDR along with the c-Met. K252 is another molecule which is also a specific c-Met inhibitor exhibited the reduced levels of oncogenesis [5].

c-MET INHIBITORS: CLINICAL TRIALS:
During the clinical trials of c-Met inhibitors different in vitro and in vivo studies were carried out to report c-Met inhibition. A lot of c-Met inhibitors showed that they are efficient during the pre-clinical trials but there is a need to analyze them in clinical studies. Various cancerous cell lines were treated with ARQ 197 and the growth and proliferation was found to be inhibited due to a check in c-Met pathway leading to apoptosis by the signaling pathway dependent upon caspases hence a constitutive activation of c-Met was observed in these cancer cells. When ARQ 197 was administered orally in different xenograft models of mouse, an inhibition in tumor growth was seen. Hence this inhibitor molecule was further evaluated in the clinical studies phase II against different types of cancers [6]. PHA665752 represented a very strong inhibition of c-Met both biochemically and biologically in the Met transformed cells having TPR induction. NSCLC or Non small lung cancer was also treated very effectively by using PHA665752 and Rapamycin that is an mtorc2 inhibitor, in combination with each other [7]. Hence the success of different c-Met inhibitors in the pre-clinical trials has produced their chances to further move for the clinical trials of cancer.

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.
S1039	Rapamycin (Sirolimus)	Rapamycin (Sirolimus) is a specific mTOR inhibitor with IC50 of ~0.1 nM HEK293 cells.Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1. Rapamycin is an autophagy activator and an immunosuppressant.