title: SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo.
abstract: 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.
authors.affiliation: SGX Pharmaceuticals, San Diego, CA 92121, USA. buchanan_sean@lilly.com
authors.forename: Sean G
authors.initials: SG
authors.lastname: Buchanan
authors.forename: Jorg
authors.initials: J
authors.lastname: Hendle
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Lee
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Smith
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bounaud
authors.forename: Katti A
authors.initials: KA
authors.lastname: Jessen
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Tang
authors.forename: Nanni H
authors.initials: NH
authors.lastname: Huser
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Felce
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Froning
authors.forename: Marshall C
authors.initials: MC
authors.lastname: Peterman
authors.forename: Brandon E
authors.initials: BE
authors.lastname: Aubol
authors.forename: Steve F
authors.initials: SF
authors.lastname: Gessert
authors.forename: J Michael
authors.initials: JM
authors.lastname: Sauder
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Schwinn
authors.forename: Marijane
authors.initials: M
authors.lastname: Russell
authors.forename: Isabelle A
authors.initials: IA
authors.lastname: Rooney
authors.forename: Jason
authors.initials: J
authors.lastname: Adams
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Leon
authors.forename: Tuan H
authors.initials: TH
authors.lastname: Do
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Blaney
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sprengeler
authors.forename: Devon A
authors.initials: DA
authors.lastname: Thompson
authors.forename: Lydia
authors.initials: L
authors.lastname: Smyth
authors.forename: Laura A
authors.initials: LA
authors.lastname: Pelletier
authors.forename: Shane
authors.initials: S
authors.lastname: Atwell
authors.forename: Kevin
authors.initials: K
authors.lastname: Holme
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wasserman
authors.forename: Spencer
authors.initials: S
authors.lastname: Emtage
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Burley
authors.forename: Siegfried H
authors.initials: SH
authors.lastname: Reich
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002384:Catalysis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C547925:6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014230:Triazoles; D000255:Adenosine Triphosphate; D019859:Proto-Oncogene Proteins c-met