title: In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase.
abstract: IGF-IR-mediated signaling promotes survival, anchorage-independent growth, and oncogenic transformation, as well as tumor growth and metastasis formation in vivo. NVP-AEW541 is a pyrrolo[2,3-d]pyrimidine derivative small molecular weight kinase inhibitor of the IGF-IR, capable of distinguishing between the IGF-IR (IC50 = 0.086 microM) and the closely related InsR (IC50 = 2.3 microM) in cells. As expected for a specific IGF-IR kinase inhibitor, NVP-AEW541 abrogates IGF-I-mediated survival and colony formation in soft agar at concentrations that are consistent with inhibition of IGF-IR autophosphorylation. In vivo, this orally bioavailable compound inhibits IGF-IR signaling in tumor xenografts and significantly reduces the growth of IGF-IR-driven fibrosarcomas. Thus, NVP-AEW541 represents a class of selective, small molecule IGF-IR kinase inhibitors with proven in vivo antitumor activity and potential therapeutic application.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Echeverría
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pearson
authors.forename: Andreas
authors.initials: A
authors.lastname: Marti
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.forename: Juergen
authors.initials: J
authors.lastname: Mestan
authors.forename: Johann
authors.initials: J
authors.lastname: Zimmermann
authors.forename: Jiaping
authors.initials: J
authors.lastname: Gao
authors.forename: Josef
authors.initials: J
authors.lastname: Brueggen
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Capraro
authors.forename: Robert
authors.initials: R
authors.lastname: Cozens
authors.forename: Dean B
authors.initials: DB
authors.lastname: Evans
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Diana Graus
authors.initials: DG
authors.lastname: Porta
authors.forename: Janis
authors.initials: J
authors.lastname: Liebetanz
authors.forename: Georg
authors.initials: G
authors.lastname: Martiny-Baron
authors.forename: Stephan
authors.initials: S
authors.lastname: Ruetz
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism*; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D019061:src-Family Kinases