Open AccessJournal Article
A Selective Small Molecule Inhibitor of c-Met Kinase Inhibits c-Met-Dependent Phenotypes in Vitro and Exhibits Cytoreductive Antitumor Activity in Vivo
James G. Christensen,Randall E. Schreck,Jon Burrows,Poonam Kuruganti,Emily Chan,Phuong Le,Jeffrey H. Chen,Xueyan Wang,Lany Ruslim,Robert A. Blake,Kenneth E. Lipson,John Ramphal,Steven Do,Jingrong Jean Cui,Julie M. Cherrington,Dirk B. Mendel +15 more
TLDR
The feasibility of selectively targeting c-Met with ATP-competitive small-molecules with high selectivity is demonstrated and the therapeutic potential of targetingc-Met in human cancers is suggested.Abstract:
The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the development and progression of several human cancers and are attractive targets for cancer therapy. PHA-665752 was identified as a small molecule, ATP-competitive, active-site inhibitor of the catalytic activity of c-Met kinase ( K i 4 nm). PHA-665752 also exhibited >50-fold selectivity for c-Met compared with a panel of diverse tyrosine and serine-threonine kinases. In cellular studies, PHA-665752 potently inhibited HGF-stimulated and constitutive c-Met phosphorylation, as well as HGF and c-Met-driven phenotypes such as cell growth (proliferation and survival), cell motility, invasion, and/or morphology of a variety of tumor cells. In addition, PHA-665752 inhibited HGF-stimulated or constitutive phosphorylation of mediators of downstream signal transduction of c-Met, including Gab-1, extracellular regulated kinase, Akt, signal transducer and activator of transcription 3, phospholipase C γ, and focal adhesion kinase, in multiple tumor cell lines in a pattern correlating to the phenotypic response of a given tumor cell. In in vivo studies, a single dose of PHA-665752 inhibited c-Met phosphorylation in tumor xenografts for up to 12 h. Inhibition of c-Met phosphorylation was associated with dose-dependent tumor growth inhibition/growth delay over a repeated administration schedule at well-tolerated doses. Interestingly, potent cytoreductive activity was demonstrated in a gastric carcinoma xenograft model. Collectively, these results demonstrate the feasibility of selectively targeting c-Met with ATP-competitive small-molecules and suggest the therapeutic potential of targeting c-Met in human cancers.read more
Citations
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Journal ArticleDOI
MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Jeffrey A. Engelman,Kreshnik Zejnullahu,Tetsuya Mitsudomi,Youngchul Song,Courtney Hyland,Joon Oh Park,Neal I. Lindeman,Christopher-Michael Gale,Xiaojun Zhao,James J. Christensen,Takayuki Kosaka,Alison J. Holmes,Andrew M. Rogers,Federico Cappuzzo,Tony Mok,Charles Lee,Bruce E. Johnson,Lewis C. Cantley,Pasi A. Jänne +18 more
TL;DR: It is proposed that MET amplification may promote drug resistance in other ERBB-driven cancers as well after it was found that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors.
PatentDOI
Tyrosine kinase inhibitors
TL;DR: In this article, the imidazo[1,2-a]pyrimidine derivatives are used for treating cellular proliferative diseases, for treating disorders associated with MET activity, and for inhibiting the receptor tyrosine kinase MET.
Journal ArticleDOI
Cabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor Growth
F. Michael Yakes,Jason Chen,Jenny Tan,Kyoko Yamaguchi,Yongchang Shi,Peiwen Yu,Fawn Qian,Felix Chu,Frauke Bentzien,Belinda Cancilla,Jessica Orf,Andrew You,A. Douglas Laird,Stefan Engst,Lillian Lee,Justin Lesch,Yu-Chien Chou,Alison Joly +17 more
TL;DR: Treatment with cabozantinib is suggested to be a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling.
Journal ArticleDOI
Can we safely target the WNT pathway
TL;DR: The problems and potential solutions to the vexing situation of aberrant regulation of the WNT pathway are examined and a attempt is made to bring them into perspective.
Journal ArticleDOI
Drug development of MET inhibitors : targeting oncogene addiction and expedience
TL;DR: Recent progress in the development of molecules that inhibit MET function are discussed and their application in a subset of human tumours that are potentially responsive to MET-targeted therapies is considered.
References
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Journal ArticleDOI
Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product
Donald P. Bottaro,Jeffrey S. Rubin,D. L. Faletto,Andrew K Chan,Thomas E. Kmiecik,G F Vande Woude,Stuart A. Aaronson +6 more
TL;DR: A 145-kilodalton tyrosyl phosphoprotein observed in rapid response to HGF treatment of intact target cells was identified by immunoblot analysis as the beta subunit of the c-met proto-oncogene product, a membrane-spanning tyrosine kinase.
Journal ArticleDOI
Scatter factor/hepatocyte growth factor is essential for liver development
C Schmidt,Friedhelm Bladt,S Goedecke,Volker Brinkmann,W Zschiesche,M Sharpe,Ermanno Gherardi,Carmen Birchmeier +7 more
TL;DR: It is reported that mice lacking SF/HGF fail to complete development and die in utero, and the mutation affects the embryonic liver, which is reduced in size and shows extensive loss of parenchymal cells.
Journal ArticleDOI
Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas
Laura S. Schmidt,Fuh Mei Duh,F. Chen,Takeshi Kishida,Gladys Glenn,Peter L. Choyke,Stephen W. Scherer,Zhengping Zhuang,Irina A. Lubensky,Michael Dean,Rando Allikmets,Abirami Chidambaram,Ulf S.R. Bergerheim,J. T. Feltis,C. Casadevall,A. Zamarron,M. Bernues,Stéphane Richard,C. J. M. Lips,McClellan M. Walther,Lap-Chee Tsui,Laura Geil,Mary Lou Orcutt,Thomas Stackhouse,J. Lipan,L. Slife,Hiltrud Brauch,Jochen Decker,G. Niehans,M. D. Hughson,Holger Moch,Stefan Storkel,Michael I. Lerman,W.M. Linehan,B. Zbar +34 more
TL;DR: The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.
Journal ArticleDOI
Scatter factor is a fibroblast-derived modulator of epithelial cell mobility.
TL;DR: The scatter factor is a paracrine effector of epithelial-mesenchymal interaction, which affects the intercellular connections and mobility of normal epithelial cells, and might be involved in epithelial migration.
Journal ArticleDOI
Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud.
TL;DR: It is reported that the c-met-encoded receptor tyrosine kinase is essential for migration of myogenic precursor cells into the limb anlage and for migration into diaphragm and tip of tongue.
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