c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations |
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Authors: | Bellon Steven F Kaplan-Lefko Paula Yang Yajing Zhang Yihong Moriguchi Jodi Rex Karen Johnson Carol W Rose Paul E Long Alexander M O'Connor Anne B Gu Yan Coxon Angela Kim Tae-Seong Tasker Andrew Burgess Teresa L Dussault Isabelle |
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Affiliation: | Department of Molecular Structure, Amgen Inc., Thousand Oaks, CA 91320, USA. |
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Abstract: | 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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