Carroll M, Ohno-Jones S, Tamura S, Buchdunger E, Zimmermann J, Lydon N B, Gilliland D G, Druker B J
Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, Oregon 97201-3098, USA.
Blood. 1997 Dec 15;90(12):4947-52.
CGP 57148 is a compound of the 2-phenylaminopyrimidine class that selectively inhibits the tyrosine kinase activity of the ABL and the platelet-derived growth factor receptor (PDGFR) protein tyrosine kinases. We previously showed that CGP 57148 selectively kills p210BCR-ABL-expressing cells. To extend these observations, we evaluated the ability of CGP 57148 to inhibit other activated ABL tyrosine kinases, including p185BCR-ABL and TEL-ABL. In cell-based assays of ABL tyrosine phosphorylation, inhibition of ABL kinase activity was observed at concentrations similar to that reported for p210BCR-ABL. Consistent with the in vitro profile of this compound, the growth of cells expressing activated ABL protein tyrosine kinases was inhibited in the absence of exogenous growth factor. Growth inhibition was also observed with a p185BCR-ABL-positive acute lymphocytic leukemia (ALL) cell line generated from a Philadelphia chromosome-positive ALL patient. As CGP 57148 inhibits the PDGFR kinase, we also showed that cells expressing an activated PDGFR tyrosine kinase, TEL-PDGFR, are sensitive to this compound. Thus, this compound may be useful for the treatment of a variety of BCR-ABL-positive leukemias and for treatment of the subset of chronic myelomonocytic leukemia patients with a TEL-PDGFR fusion protein.
CGP 57148是一种2-苯基氨基嘧啶类化合物，可选择性抑制ABL的酪氨酸激酶活性以及血小板衍生生长因子受体（PDGFR）蛋白酪氨酸激酶。我们之前表明，CGP 57148可选择性杀死表达p210BCR-ABL的细胞。为扩展这些观察结果，我们评估了CGP 57148抑制其他活化ABL酪氨酸激酶的能力，包括p185BCR-ABL和TEL-ABL。在基于细胞的ABL酪氨酸磷酸化检测中，在与报道的p210BCR-ABL相似的浓度下观察到ABL激酶活性受到抑制。与该化合物的体外特性一致，在无外源性生长因子的情况下，表达活化ABL蛋白酪氨酸激酶的细胞生长受到抑制。在一株源自费城染色体阳性的急性淋巴细胞白血病（ALL）患者的p185BCR-ABL阳性ALL细胞系中也观察到生长抑制。由于CGP 57148抑制PDGFR激酶，我们还表明，表达活化PDGFR酪氨酸激酶TEL-PDGFR的细胞对该化合物敏感。因此，该化合物可能对治疗多种BCR-ABL阳性白血病以及治疗伴有TEL-PDGFR融合蛋白的慢性粒单核细胞白血病患者亚群有用。
