A Selective Small Molecule Inhibitor of c-Met, PHA665752, Inhibits Tumorigenicity and Angiogenesis in Mouse Lung Cancer Xenografts

Puri, Neelu; Khramtsov, Andrey; Ahmed, Salman; Nallasura, Vidya; Hetzel, Jeremy T.; Jagadeeswaran, Ramasamy; Karczmar, G. S.; Salgia, Ravi

doi:10.1158/0008-5472.can-06-4416

Cited by 115 publications

(87 citation statements)

References 13 publications

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“…Interestingly, treatment of mice using a daily schedule of 60 mg/ kg was also highly effective in retarding tumor growth despite incomplete target inhibition through the entire 24 h dosing interval. Xenografts derived from U87MG human glioblastoma cells, which activate MET by an autocrine mechanism (8), and H441 human lung cancer cells, which express phospho-MET (34), are sensitive to multitargeted kinase inhibitors (14,15,34). The growth of U87MG tumors is additionally impeded by ribozymes and antibodies directed at HGF (9,10) or MET (9,12).…”

Section: Sgx523 Inhibits Met But Not Other Kinases In Cellsmentioning

confidence: 99%

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo

Buchanan¹,

Hendle²,

Lee³

et al. 2009

Molecular Cancer Therapeutics

122

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The MET receptor tyrosine kinase has emerged as an important target for the development of novel cancer therapeutics. Activation of MET by mutation or gene amplification has been linked to kidney, gastric, and lung cancers. In other cancers, such as glioblastoma, autocrine activation of MET has been demonstrated. Several classes of ATP-competitive inhibitor have been described, which inhibit MET but also other kinases. Here, we describe SGX523, a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC 50 of 4 nmol/L and is >1,000-fold selective versus the >200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited MET-mediated signaling, cell proliferation, and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition. [Mol Cancer Ther 2009;8(12):3181-90]

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Section: Sgx523 Inhibits Met But Not Other Kinases In Cellsmentioning

confidence: 99%

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo

Buchanan¹,

Hendle²,

Lee³

et al. 2009

Molecular Cancer Therapeutics

122

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“…Early Phase Ⅱ data on renal cell cancer has been positive [37] . It has shown activity in lung cancer (both small cell and non-small cell) xenografts in immunocompromised mice [38] . Additional tyrosine kinase inhibitors that are specific to the c-Met receptor have been developed [39][40][41] .…”

Section: Cholangiocarcinomamentioning

confidence: 99%

“…Partial responses and durable long term disease control have been achieved in several malignancies [42] . PHA665752 is a selective small molecule tyrosine kinase inhibitor of c-Met [38,43] . It has been shown to inhibit angiogenesis and induce apoptosis and cell cycle arrest.…”

Section: Cholangiocarcinomamentioning

confidence: 99%

c-Met targeted therapy of cholangiocarcinoma

Socoteanu¹,

Mott²,

Alpini³

et al. 2008

WJG

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Cholangiocarcinoma continues to be a challenging disease to treat. Systemic therapy is used in unresectable disease, disease progression after surgery, and in the palliative setting. Unfortunately, results of multiple phase Ⅱ trials have rarely yielded positive results. As data on the molecular carcinogenesis of cholangiocarcinoma is developing, we are more able to understand the disease process and can use this understanding to create unique targeted therapies. We reviewed the role of c-Met/ hepatocyte growth factor (HGF) in the development of cholangiocarcinoma. Furthermore, we explored the use of the c-Met guided cascade as a target to treat cholangiocarcinoma. We reviewed the current use and options for future development of c-Met agents to treat this disease.

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“…Therefore, we investigated the role of RPTP-␤ in the regulation of keratinocyte proliferation and migration. We found that blockade of Met tyrosine kinase activity by a specific inhibitor (47,48) suppressed proliferation of primary human keratinocytes (Fig. 8A).…”

Section: Rptp-␤ Regulates Met-mediated Proliferation and Migration Inmentioning

confidence: 82%

Receptor-type Protein Tyrosine Phosphatase β (RPTP-β) Directly Dephosphorylates and Regulates Hepatocyte Growth Factor Receptor (HGFR/Met) Function

Xia

Baker

et al. 2011

Journal of Biological Chemistry

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Protein tyrosine phosphorylation is a ubiquitous, fundamental biochemical mechanism that regulates essential eukaryotic cellular functions. The level of tyrosine phosphorylation of specific proteins is finely tuned by the dynamic balance between protein tyrosine kinase and protein tyrosine phosphatase activities. Hepatocyte growth factor receptor (also known as Met), a receptor protein tyrosine kinase, is a major regulator of proliferation, migration, and survival for many epithelial cell types. We report here that receptor-type protein tyrosine phosphatase ␤ Hepatocyte growth factor (HGF)3 , also known as scatter factor, is expressed in numerous tissues (1-5) and participates in the regulation of angiogenesis, organogenesis, tissue repair, and neural induction (6). HGF induces random movement/scattering in epithelial cells as well as dissociation, migration, and invasion of cells through the extracellular matrix in vivo (7,8). HGF is mitogenic in many normal cell types, including epithelial cells, vascular endothelial cells, and melanocytes. HGF is also a morphogen that induces transition of epithelial cells into a mesenchymal morphology and formation of branched tubelike structures (9, 10). In keratinocytes, HGF has been shown to promote motility and proliferation (11,12). Each of these biological effects exerted by HGF is triggered by stimulation of its cell surface receptor, Met (also known as HGF receptor), with concomitant activation of downstream effecter molecules (8,13,14).Upon ligand binding, Met autophosphorylates several tyrosine residues in its carboxyl-terminal domain. Met function is controlled by its state of tyrosine phosphorylation (15-17). Among the tyrosines within the carboxyl terminus, phosphorylation of tyrosines 1234 and 1235, located within the catalytic domain, is required for tyrosine kinase activity (15-17). Phosphorylation of tyrosines 1349 and 1356, which are highly conserved among other members of the Met family, such as Sea and Ron, are necessary for most biological activities of . Tyrosines 1349 and 1356, when phosphorylated, serve as multifunctional binding sites for Gab1, Grab2, PI3K, phospholipase C-␥, SHP2, and Cbl proto-oncogene. Phosphorylation of tyrosine 1356 is essential for transducing signals for cell motility and morphogenesis (19 -21).In addition to its roles in many normal physiological processes, Met also plays important roles in human malignancy. Met was originally identified as the TPR-Met oncogene, which possesses ligand-independent tyrosine kinase activity. TPR-Met arises from chromosomal fusion of the translocated promoter region (TPR) in chromosome 1 with the Met carboxyl-terminal sequence on chromosome 7 (22, 23). This rearrangement has been observed in patients with gastric carcinoma (24). A large body of evidence demonstrates that misregulation of the Met signaling pathway is involved in many types of human cancers. Inappropriate expression of HGF/Met autocrine signaling confers increased tumorigenesis and metastatic activity in vivo, and Met expression o...

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A Selective Small Molecule Inhibitor of c-Met, PHA665752, Inhibits Tumorigenicity and Angiogenesis in Mouse Lung Cancer Xenografts

Cited by 115 publications

References 13 publications

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo

c-Met targeted therapy of cholangiocarcinoma

Receptor-type Protein Tyrosine Phosphatase β (RPTP-β) Directly Dephosphorylates and Regulates Hepatocyte Growth Factor Receptor (HGFR/Met) Function

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