CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins
CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins
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DOI：
10.1182/blood.v90.12.4947.4947_4947_4952
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发表时间：
1997-12-15
期刊：
影响因子：
20.3
通讯作者：
Druker, BJ
中科院分区：
文献类型：
--
作者：
Carroll, M;OhnoJones, S;Druker, BJ
Cop 57148是一种2-苯氨基嘧啶类化合物，可选择性抑制ABL和血小板衍生生长因子受体（PDGFR）蛋白酪氨酸激酶的酪氨酸激酶活性。为了扩展这些观察结果，我们评价了CGP 57148抑制其它活化的ABL酪氨酸激酶，包括p185 BCR-ABL和TEL-ABL的能力。在基于细胞的ABL酪氨酸磷酸化测定中，在与p210 BCR-ABL相似的浓度下观察到ABL激酶活性的抑制，与该化合物的体外特征一致，表达活化的ABL蛋白酪氨酸激酶的细胞的生长在不存在外源生长因子的情况下被抑制。从费城染色体阳性ALL患者产生的p185 BCR-ABL阳性急性淋巴细胞白血病（ALL）细胞系也观察到生长抑制。由于Cop 57148抑制PDGFR激酶，我们还表明表达活化的PDGFR酪氨酸激酶TEL-PDGFR的细胞对该化合物敏感。因此，该化合物可用于治疗多种BCR-ABL阳性白血病和治疗具有TEL-PDGFR融合蛋白的慢性粒单核细胞白血病患者的亚群，（C）1997，美国血液学会。
Cop 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 Cop 57148 selectively kilts 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 Cop 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, (C) 1997 by The American Society of Hematology.