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J. Biol. Chem., Vol. 283, Issue 5, 2675-2683, February 1, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/5/2675    most recent M705774200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bellon, S. F. Articles by Dussault, I. PubMed PubMed Citation Articles by Bellon, S. F. Articles by Dussault, I. Social Bookmarking                      What's this?

c-Met Inhibitors with Novel Binding Mode Show Activity against Several Hereditary Papillary Renal Cell Carcinoma-related Mutations^*

Steven F. Bellon, Paula Kaplan-Lefko, Yajing Yang, Yihong Zhang, Jodi Moriguchi, Karen Rex, Carol W. Johnson^¶, Paul E. Rose, Alexander M. Long, Anne B. O'Connor, Yan Gu, Angela Coxon, Tae-Seong Kim^||, Andrew Tasker^||, Teresa L. Burgess, and Isabelle Dussault¹

From the Departments of Molecular Structure, Oncology Research, ^¶Pathology, and ^||Medicinal Chemistry, Amgen Inc., Thousand Oaks, California 91320

c-Met is a receptor tyrosine kinase often deregulated in human cancers, thus making it an attractive drug target. One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations. Therefore, small molecules capable of targeting these mutations could offer therapeutic benefits for affected patients. SU11274 was recently described and reported to inhibit the activity of the wild-type and some mutant forms of c-Met, whereas other mutants are resistant to inhibition. We identified a novel series of c-Met small molecule inhibitors that are active against multiple mutants previously identified in hereditary papillary renal cell carcinoma patients. AM7 is active against wild-type c-Met as well as several mutants, inhibits c-Met-mediated signaling in MKN-45 and U-87 MG cells, and inhibits tumor growth in these two models grown as xenografts. The crystal structures of AM7 and SU11274 bound to unphosphorylated c-Met have been determined. The AM7 structure reveals a novel binding mode compared with other published c-Met inhibitors and SU11274. The molecule binds the kinase linker and then extends into a new hydrophobic binding site. This binding site is created by a significant movement of the C-helix and so represents an inactive conformation of the c-Met kinase. Thus, our results demonstrate that it is possible to identify and design inhibitors that will likely be active against mutants found in different cancers.

Received for publication, July 13, 2007 , and in revised form, November 28, 2007.

The atomic coordinates and structure factors (code 2RFN and 2RFS) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320-1799. Fax: 805-375-8368; E-mail: idussaul{at}amgen.com.

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