Quintás-Cardama Alfonso, Kantarjian Hagop, Cortes Jorge
Department of Leukemia, Unit 428, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA.
Nat Rev Drug Discov. 2007 Oct;6(10):834-48. doi: 10.1038/nrd2324.
The introduction of the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec; Novartis) revolutionized the treatment of chronic myeloid leukaemia (CML). However, most patients with CML receiving imatinib still harbour molecular residual disease and some develop resistance associated with ABL kinase domain mutations. The second-generation BCR-ABL inhibitors nilotinib (Tasigna; Novartis) and dasatinib (Sprycel; Bristol-Myers Squibb) have shown significant activity after imatinib failure in clinical trials, but still face similar obstacles to imatinib, including negligible activity against the frequent BCR-ABL T315I mutation and modest effects in advanced phases of CML. Various medicinal chemistry efforts, in part aided by structural studies of the ABL kinase-imatinib complex have resulted in the synthesis of a new generation of BCR-ABL inhibitors, some of which have shown encouraging preliminary activity in clinical trials, including against T315I mutants. Here, we discuss these emerging therapies, which have the potential to improve the outcome of patients with CML.
BCR-ABL激酶抑制剂甲磺酸伊马替尼（格列卫；诺华公司）的问世彻底改变了慢性髓性白血病（CML）的治疗方式。然而，大多数接受伊马替尼治疗的CML患者仍存在分子残留病，部分患者会出现与ABL激酶结构域突变相关的耐药性。第二代BCR-ABL抑制剂尼罗替尼（达希纳；诺华公司）和达沙替尼（施达赛；百时美施贵宝公司）在临床试验中显示出在伊马替尼治疗失败后具有显著活性，但仍面临与伊马替尼类似的障碍，包括对常见的BCR-ABL T315I突变活性可忽略不计以及在CML晚期效果有限。借助ABL激酶-伊马替尼复合物的结构研究，各种药物化学研究工作已促成新一代BCR-ABL抑制剂的合成，其中一些在临床试验中已显示出令人鼓舞的初步活性，包括对T315I突变体的活性。在此，我们讨论这些新兴疗法，它们有可能改善CML患者的治疗结果。
