K252a is a selective inhibitor of the tyrosine protein kinase activity of the trk family of oncogenes and neurotrophin receptors.
K252a, an efficient serine/threonine protein kinase inhibitor (IC50s of 10 to 30 nM), has been shown to block the neuronal differentiation of rat pheochromocytoma PC12 cells induced by nerve growth factor (NGF). In this report, we demonstrate that K252a is a potent inhibitor (IC50 of 3 nM) of the tyrosine protein kinase activity of the NGF receptor gp140trk, the product of the trk protooncogene. K252a also inhibits the kinase activity of its transforming alleles, the trk oncogenes, and of the related neurotrophin receptors gp145trkB and gp145trkC, the products of the other known members of the trk gene family, trkB and trkC. In contrast, K252a has no effect (even at micromolar concentrations) on other tyrosine protein kinases such as the receptors for EGF and PDGF and the products of the v-src and v-fms oncogenes. In addition, K252a rapidly reverts the transformed phenotype of NIH3T3 cells transformed by either autocrine stimulation of the trk family of receptors by their cognate ligands or by expression of trk oncogenes isolated from human tumors. The selectivity of K252a for the catalytic activity of the trk family of kinases should help to establish the structural basis for the rational design of highly specific tyrosine protein kinase inhibitors.
Tapley
P
P
Department of Molecular Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Lamballe
F
F
Barbacid
M
M
D016475:3T3 Cells; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D026121:Indole Alkaloids; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009414:Nerve Growth Factors / Q000502:physiology; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors*; D009857:Oncogenes; D010673:Pheochromocytoma / Q000473:pathology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D017475:Receptors, Nerve Growth Factor; D014407:Tumor Cells, Cultured
D002227:Carbazoles; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; D015513:Oncogene Proteins; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; C065400:oncogene protein trk; C049985:staurosporine aglycone; D011505:Protein-Tyrosine Kinases