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

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  Publication Details (including relevant citation   information):

  Mol Cancer Ther (2009) 8: 3181-3190.

  Buchanan SG, Hendle J, Lee PS, Smith CR, Bounaud PY, Jessen KA,   Tang CM, Huser NH, Felce JD, Froning KJ, Peterman MC, Aubol BE,   Gessert SF, Sauder JM, Schwinn KD, Russell M, Rooney IA, Adams J,   Leon BC, Do TH, Blaney JM, Sprengeler PA, Thompson DA, Smyth L,   Pelletier LA, Atwell S, Holme K, Wasserman SR, Emtage S, Burley   SK, Reich SH


  The MET receptor tyrosine kinase has emerged as an important   target for  the development of novel cancer therapeutics.   Activation of MET by  mutation or gene amplification has   been linked to kidney, gastric, and  lung cancers. In other   cancers, such as glioblastoma, autocrine  activation of MET   has been demonstrated. Several classes of  ATP-competitive   inhibitor have been described, which inhibit MET but  also   other kinases. Here, we describe SGX523, a novel,   ATP-competitive  kinase inhibitor remarkable for its   exquisite selectivity for MET.  SGX523 potently inhibited   MET with an IC50 of 4 nmol/L and is  >1,000-fold   selective versus the >200-fold selectivity of other    protein kinases tested in biochemical assays. Crystallographic   study  revealed that SGX523 stabilizes MET in a unique   inactive conformation  that is inaccessible to other protein   kinases, suggesting an explanation  for the selectivity.   SGX523 inhibited MET-mediated signaling, cell    proliferation, and cell migration at nanomolar concentrations but   had no  effect on signaling dependent on other protein   kinases, including the  closely related RON, even at   micromolar concentrations. SGX523  inhibition of MET in vivo   was associated with the dose-dependent  inhibition of growth   of tumor xenografts derived from human glioblastoma  and   lung and gastric cancers, confirming the dependence of these   tumors  on MET catalytic activity. Our results show that   SGX523 is the most  selective inhibitor of MET catalytic   activity described to date and is  thus a useful tool to   investigate the role of MET kinase in cancer  without the   confounding effects of promiscuous protein kinase    inhibition.

  Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/19934279