c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma related mutations

doi:10.1074/jbc.M705774200

HOME

QUICK SEARCH:

	Author:		Keyword(s):
Year:		Vol:		Page:

A more recent version of this article appeared on February 1, 2008

This Article

	Full Text (Accepted Manuscript)
	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

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
	Request Permissions

Citing Articles

	Citing Articles via HighWire
	Citing Articles via Google Scholar

Google Scholar

	Articles by Bellon, S. F.
	Articles by Dussault, I.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Bellon, S. F.
	Articles by Dussault, I.

Social Bookmarking

	What's this?

Papers In Press, published online ahead of print November 30, 2007
J. Biol. Chem, 10.1074/jbc.M705774200
Submitted on July 13, 2007
Revised on November 28, 2007
Accepted on November 30, 2007

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 Dussault

Oncology research, Amgen Inc., Thousand Oaks, CA 91320-1799

Corresponding Author: idussaul{at}amgen.com

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 while 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.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

M. J. Binning, T. Niazi, C. A. Pedone, B. Lal, C. G. Eberhart, K. J. Kim, J. Laterra, and D. W. Fults
Hepatocyte Growth Factor and Sonic Hedgehog Expression in Cerebellar Neural Progenitor Cells Costimulate Medulloblastoma Initiation and Growth
Cancer Res., October 1, 2008; 68(19): 7838 - 7845.
[Abstract] [Full Text] [PDF]

L. Toschi and P. A. Janne
Single-Agent and Combination Therapeutic Strategies to Inhibit Hepatocyte Growth Factor/MET Signaling in Cancer
Clin. Cancer Res., October 1, 2008; 14(19): 5941 - 5946.
[Abstract] [Full Text] [PDF]

D. Choquette, L. Liu, T.-S. Kim, M. Norman, A. Siegmund, N. Xi, S. F Bellon, A. Chen, P. Kaplan-Lefko, M. Lee, et al.
Discovery of AMG 458: A Potent, Selective, and Orally Bioavailable c-Met Inhibitor
Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 713 - 718.
[Abstract] [Full Text] [PDF]