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2rfn

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{{STRUCTURE_2rfn| PDB=2rfn | SCENE= }}
{{STRUCTURE_2rfn| PDB=2rfn | SCENE= }}
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'''x-ray structure of c-Met with inhibitor.'''
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===x-ray structure of c-Met with inhibitor.===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 18055465 is the PubMed ID number.
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{{ABSTRACT_PUBMED_18055465}}
==Disease==
==Disease==
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[[Category: Transmembrane]]
[[Category: Transmembrane]]
[[Category: Tyrosine-protein kinase]]
[[Category: Tyrosine-protein kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 16 23:08:08 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 08:50:30 2008''

Revision as of 05:50, 29 July 2008

Image:2rfn.png

Template:STRUCTURE 2rfn

Contents

x-ray structure of c-Met with inhibitor.

Template:ABSTRACT PUBMED 18055465

Disease

Known disease associated with this structure: Hepatocellular carcinoma, childhood type OMIM:[164860], Renal cell carcinoma, papillary, familial and sporadic OMIM:[164860], Autism, suseptibility to, 9 OMIM:[164860]

About this Structure

2RFN is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations., Bellon SF, Kaplan-Lefko P, Yang Y, Zhang Y, Moriguchi J, Rex K, Johnson CW, Rose PE, Long AM, O'Connor AB, Gu Y, Coxon A, Kim TS, Tasker A, Burgess TL, Dussault I, J Biol Chem. 2008 Feb 1;283(5):2675-83. Epub 2007 Nov 30. PMID:18055465

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