CEP-751 inhibits TRK receptor tyrosine kinase activity in vitro exhibits anti-tumor activity.
The present report describes the in vitro and in vivo profile of CEP-751, a novel receptor tyrosine kinase inhibitor. CEP-751 at 100 nM inhibits the receptor tyrosine kinase activity of the neurotrophin receptors trkA, trkB and trkC. CEP-751 has no effect on activity of receptors for EGF, IGF-I, insulin or on erbB2; inhibition of receptors for PDGF and bFGF was observed but occurred with lesser potency than inhibition of trk. CEP-751 exhibited anti-tumor efficacy against tumors derived from NIH3T3 cells transfected with trkA. Inhibition of trk phosphorylation could also be measured in these tumors, suggesting that anti-tumor efficacy of CEP-751 is related to inhibition of trk receptor tyrosine kinase activity. CEP-751 was found to be without effect when administered to nude mice bearing SK-OV-3 tumors, which overexpress erbB2 receptors, providing further evidence that inhibition of tumor growth may be related to inhibition of trk receptor tyrosine kinase activity. Our data indicate that CEP-751 is a potent trk inhibitor which possesses anti-tumor activity.
Camoratto
A M
AM
Cephalon, Inc., West Chester, PA 19380, USA. acamorat@cephalon.com
Jani
J P
JP
Angeles
T S
TS
Maroney
A C
AC
Sanders
C Y
CY
Murakata
C
C
Neff
N T
NT
Vaught
J L
JL
Isaacs
J T
JT
Dionne
C A
CA
D016475:3T3 Cells / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013268:Stimulation, Chemical; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; C107558:CEP 751; D002227:Carbazoles; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D014443:Tyrosine; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA