CEP-751 INHIBITS TRK RECEPTOR TYROSINE KINASE-ACTIVITY IN-VITRO AND EXHIBITS ANTITUMOR-ACTIVITY

The present report describes the in vitro and in vivo profile of CEP-7 51, a novel receptor tyrosine kinase inhibitor. CEP-751 at 100 nM inhi bits the receptor tyrosine kinase activity of the neurotrophin recepto rs 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 inhibitio n of trk. CEP-751 exhibited anti-tumor efficacy against tumors derived from NIH3T3 cells transfected with trkA. Inhibition of trk phosphoryl ation could also be measured in these tumors, suggesting that anti-tum or efficacy of CEP-751 is related to inhibition of trk receptor tyrosi ne kinase activity. CEP-751 was found to be without effect when admini stered to nude mice bearing SK-OV-3 tumors, which overexpress erbB2 re ceptors, providing further evidence that inhibition of tumor growth ma y be related to inhibition of trk receptor tyrosine kinase activity. O ur data indicate that CEP-751 is a potent trk inhibitor which possesse s anti-tumor activity. (C) 1997 Wiley-Liss, Inc.