In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase.
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.
García-Echeverría
Carlos
C
Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
Pearson
Mark A
MA
Marti
Andreas
A
Meyer
Thomas
T
Mestan
Juergen
J
Zimmermann
Johann
J
Gao
Jiaping
J
Brueggen
Josef
J
Capraro
Hans-Georg
HG
Cozens
Robert
R
Evans
Dean B
DB
Fabbro
Doriano
D
Furet
Pascal
P
Porta
Diana Graus
DG
Liebetanz
Janis
J
Martiny-Baron
Georg
G
Ruetz
Stephan
S
Hofmann
Francesco
F
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
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D019061:src-Family Kinases