Bms-777607 Serve As A Strong Inhibitor For Prostate Tumors Or Cancer Cells

INTRODUCTION

Receptor of hepatocyte growth factor (HGFR) is encoded by a gene called c-MET or MET. This is proto-oncogene and is found in variable balance in different cancer or tumor cell. In prostate cancer this gene is mostly up-regulated and has a high activity. The gene is responsible for the spreading of cancer, also called metastasis (an uncontrolled cancer condition). Same as other kinase inhibitor a small compound BMS 777607 inhibits the kinases specifically c-MET or MET. This inhibitor is thus selective for the tyrosine kinase receptor; it also affects the signaling pathway mediated by HGF [1].



CHEMISTRY OF BMS 777607

The chemical structure of BMS 777607 is important compound for its different properties like its hydrophilic nature, stronger binding with certain enzymes and selective inhibition of some kinases [2]. Tyrosine kinases use ATP (Adenosine triphosphate) as their substrate, the BMS 777607 competes with their natural substrate, and hence it is a competitor inhibitor of kinases [1]. When a concentration of about 20 nmol/L was used during research studies, it was able to stop autophosphorylation of c- Met induced by HGF. This anticancer is enlisted with other chemicals of clinical trials such as KU-55933, Abiraterone, Belinostat etc. and is in phase I. BMS 777607 has 3.9nmol/L Ki value when actively binds with the active site residues of c-MET [2].

BMS 777607: EFFECT ON MET

HGF (hepatocyte growth factor) which plays important role in the activation of c-Met in stromal cells. Its role is to stimulate the process of autophosphorylation at 1234 and 1235tyrosine residues of c-Met. The resultant action is the activation of paracrine loop. After autophosphorylation it stimulates the RAS-Akt-PI3K pathway. Another tyrosine kinase, Src is downstream to c-Met gene sequence [1]. HGF growth factor induces paracrine signaling in prostate gland. Stromal cells synthesize this hormone which affects its neighboring epithelial cells. Whenever the androgen gene expression is down-regulated it leads to high c-Met expression. The mentioned whole process depicts the role of c-Met in prostate cancer progression [3]. This is the cause of metastasis rather than tumor growth.

BMS-777607: CHECKS INVASIVE GROWTH

HGF or scatter factor is mainly the reason of invasive growth of cells. There are only few important steps in the cellular invasion including cell migration, cell adhesion and intruding via the sheet which is present under epithelial membrane. In a carcinoma cell HGF skips all these steps by inducing its avidity to various specific ligands [4]. It is reported the invasion of PC-3 cell lines is enhanced by HGF. Only few micromolar concentration of BMS-777607 is found to be enough to inhibit this invasive growth [1].

BMS-777607: INHIBTION OF CELL PROLIFERATION

Hepatocyte growth factor (HGF) also stimulates the cyclin D1 gene expression and partly induced due to ATF-2 in mice melanoma cell. The activation of ATF-2 phosphorylation is also activated by HGF through p38 MAPK intermediates along with JNK/SAPK. This in a result induces the cell proliferation by transcriptional activation [5]. During multiple studies BMS-777607 found to be significantly ineffective on the growth of cancer cells. At 3 and 10 ? mol/L concentration a significant decrease of cellular proliferation was observed [1]. The mechanism of BMS-777607 is to control the cell proliferation induced by HGF there by controlling the metastasis.

CONCLUSION

In short the small chemical compound (inhibitor) BMS-777607 serve as a strong inhibitor of MAP kinases and in prostate tumors or cancer cells, it controls the metastasis of cancer or tumor cells. As the metastasis is more lethal than benign tumors so this compound is vital against various malignancies. BMS-777607 is on its way to step ahead in clinical trials.



REFERENCES

1. Dai Y, Siemann DW. BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro. Mol Cancer Ther 2010 Jun; 9(6):1554-61.

2. Schroeder GM, An Y, et al. Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem 2009 Mar 12; 52(5):1251-4.

3. Humphrey PA, Zhu X, et al. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol 1995 Aug; 147(2):386-96.

4. Trusolino L, Cavassa S, et al. HGF/scatter factor selectively promotes cell invasion by increasing integrin avidity. The FASEB Journal 2000 Aug 1; 14(11) 1629-1640.

5. Recio JA, Merlino G. Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1. Oncogene 2002 Feb 7; 21(7):1000-8.

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