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

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.

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo

“…The novel mode of protein kinase binding we have detailed here was recently described for two other small molecules that inhibit MET and appear to rely on similar π-π interactions with Tyr 1248 (15,35). Bicyclic triazoles, chemically related to SGX523, were also described at a recent meeting (36,37).…”

“…Interestingly, treatment of mice using a daily schedule of 60 mg/ kg was also highly effective in retarding tumor growth despite incomplete target inhibition through the entire 24 h dosing interval. Xenografts derived from U87MG human glioblastoma cells, which activate MET by an autocrine mechanism (8), and H441 human lung cancer cells, which express phospho-MET (34), are sensitive to multitargeted kinase inhibitors (14,15,34). The growth of U87MG tumors is additionally impeded by ribozymes and antibodies directed at HGF (9,10) or MET (9,12).…”

“…The catalytic domain of MET exhibits features common to all protein kinases and presents a similar selectivity challenge. Not surprisingly, therefore, where selectivity has been fully evaluated, cell-permeable MET inhibitors have been shown to target multiple kinases (13)(14)(15)(16). As a consequence, where MET kinase function has been implicated in tumorigenesis through the use of such inhibitors, a role of other kinases cannot be ruled out.…”

“…In other malignancies, such as glioblastoma, autocrine activation of MET by HGF has been shown (8), and MET inhibition is effective in mouse models of glioblastoma (9)(10)(11)(12). The wealth of evidence linking MET to cancer has motivated efforts, using various strategies, to inhibit MET signaling (5,(9)(10)(11)(12)(13)(14)(15)(16).…”

Discovery of AMG 458: A Potent, Selective, and Orally Bioavailable c-Met Inhibitor

“…1) when disclosed in the patent literature (11) as a c-Met kinase inhibitor. Structural similarities with kinase inhibitors such as imatinib were observed indicating the potential for binding to the inactive form of the kinase (12). In an eff ort to reduce potential liabilities associated with the acylthiourea functionality and conformationally restrain the molecule while maintaining key hydrogen bonds with the protein; the acylthiourea was replaced with an aminoacylpyrazolone ring.…”