c-MET INHIBITORS IN CANCER TREATMENT

by Selleckchem | Jul 26 2012

APPLICATION OF c-MET INHIBITION IN CANCERS:
c-Met is a proto-oncogene which encodes HGF-R or hepatocyte growth factor receptor, hyperactivation of this gene activates certain changes such as formation of new blood vessels or angiogenesis which leads to invasive tumor growth. Met aberrant regulation reported to be a cause of many cancers such as stomach cancer, liver cancer, ovarian cancer, breast cancer, brain and thyroid cancers. Due to this characteristic of c-Met gene inhibition has become an attractive approach for therapeutic use [1]. Therefore a huge research is being done for the development of c-Met antagonists or c-Met inhibitors which have therapeutic or clinical implications [2]. In addition to this application c-Met antagonists or agonists are also being utilized for the understanding of various cellular pathways and imparting light on the interaction of other molecules with c-Met. Commercially many of these like kinase inhibitors are available from any of the suppliers and one can easily access to them.

DIFFERENT c-MET INHIBITORS:
There are different c-Met inhibitors of c-Met pathway are under process for development. A c-Met specific inhibitor named ARQ 197 is non-competitive and small molecule which shows tumor suppressing ability by selectively inhibiting of c-Met receptor tyrosine kinase or RTK. Another famous and potent c-Met inhibitor is MK-2461 which is specific as it targets RTK in phosphorylated form. Many of the mutants of Met are targeted by another inhibitor SU11274 [3]. Another small inhibitor named as PHA665752 that is characterized thoroughly and noted to affect HGF-dependent Met phosphorylation process. It is also reported that a few amplifications of Met makes tumors and cancers even more susceptible to PHA-665752 therapy [4]. These are specific inhibitors of c-Met but there are also multiple molecules which have the property to inhibit even wider activity spectrum. An example is Foretinib that checks the actions of more than one RTKs or receptor tyrosine kinases such as KDR or VEGFR2 along with c-Met. Another molecule named K252 is a specific inhibitor for c-Met which results in reduced oncogenesis [5].

c-MET INHIBITORS IN CLINICAL TRIALS:
During clinical trials studies of c-Met inhibitors various in vivo and in vitro studies were performed and c-Met inhibition was reported. Many of the c-Met inhibitors have shown their efficacy during pre-clinical trials but these are still need to be analyzed in clinical trials. Different cancer cell lines were exposed to ARQ 197 and as a result cancer cell proliferation and growth was inhibited due to checking of c-Met pathway which lead to apoptosis by caspase-dependent signaling and in this cancer cells constitutive c-Met activation was seen. ARQ 197 when orally administered in different mouse xenograft models growth of tumors seen to be inhibited. And as a result this inhibitor is being evaluated in clinical trials phase II against many of the cancer types [6]. Met transformed cells having TPR induction, PHA665752 represented and strong c-Met inhibition both biologically and biochemically. Non small lung cancer or NSCLC was also effectively treated with PHA665752 when it was used with Rapamycin which is among mTOR inhibitors [7]. So the success of various c-Met inhibitors in preclinical studies has generated their chances to go for cancer 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.