Tapley P, Lamballe F, Barbacid M
Department of Molecular Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Oncogene. 1992 Feb;7(2):371-81.
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.
K252a是一种高效的丝氨酸/苏氨酸蛋白激酶抑制剂（IC50为10至30 nM），已被证明可阻断神经生长因子（NGF）诱导的大鼠嗜铬细胞瘤PC12细胞的神经元分化。在本报告中，我们证明K252a是NGF受体gp140trk（trk原癌基因的产物）酪氨酸蛋白激酶活性的强效抑制剂（IC50为3 nM）。K252a还抑制其转化等位基因trk癌基因以及相关神经营养因子受体gp145trkB和gp145trkC（trk基因家族其他已知成员trkB和trkC的产物）的激酶活性。相比之下，K252a对其他酪氨酸蛋白激酶（如EGF和PDGF受体以及v-src和v-fms癌基因的产物）没有影响（即使在微摩尔浓度下）。此外，K252a可迅速逆转通过其同源配体自分泌刺激trk受体家族或通过表达从人类肿瘤中分离的trk癌基因而转化的NIH3T3细胞的转化表型。K252a对trk激酶家族催化活性的选择性应有助于为合理设计高度特异性酪氨酸蛋白激酶抑制剂奠定结构基础。
