新型BCR-ABL激酶抑制剂的研究进展

Advances in the study of new BCR-ABL kinase inhibitors

融合基因BCR-ABL在人体内表达的蛋白质是一种异常的酪氨酸激酶,可导致慢性髓系白血病(chronic myeloid leukemia,CML)。随着对CML发病机制的进一步研究,人们发现开发选择性抑制异常BCR-ABL酪氨酸激酶的化合物是值得关注的研究方向。前三代BCR-ABL抑制剂为正构抑制剂,该抑制剂竞争性阻断ABL蛋白酪氨酸激酶与ATP的结合,阻止其激活下游信号。第四代BCR-ABL抑制剂通过与肉豆蔻酰口袋结合,变构抑制ABL蛋白酪氨酸激酶,具有更强的选择性且保持对耐药性突变蛋白的活性。蛋白水解靶向嵌合(proteolytic targeting chimera,PROTAC)、共价抑制剂和双重靶向抑制剂等新型药物设计策略也为BCR-ABL激酶抑制剂的开发提供了新的方向。本文综述了近年来有关BCR-ABL激酶抑制剂的研究进展,并讨论了各种新型BCR-ABL抑制剂的药物设计策略。

The oncogenic product of BCR-ABL is an abnormal tyrosine kinase that causes chronic myeloid leukemia(CML).With further research into the pathogenesis of CML,the discovery of compounds that selectively inhibit abnormal BCR-ABL tyrosine kinases is a research focus worthy of attention.The first three generations of BCR-ABL inhibitors are orthosteric inhibitors,which competitively block the binding of ABL protein tyrosine kinase to ATP and prevent it from activating downstream signals.The fourth-generation BCR-ABL inhibitors allosterically inhibit ABL protein tyrosine kinase by binding to the myristoyl pocket,providing greater selectivity and maintaining activity against drug-resistant mutations proteins.Novel drug design strategies such as proteolytic targeting chimera(PROTAC),covalent inhibitors and dual targeting inhibitors also provide new directions for the development of BCR-ABL kinase inhibitors.This paper reviews recent research advances on BCR-ABL kinase inhibitors and discusses drug design strategies for various novel BCR-ABL inhibitors.