Abstract：
Chronic myeloid leukemia (CML) is a malignant disease of the hematopoietic system with crucial pathogenic protein named BCR-ABL, which endangers the life of patients severely. As a milestone of targeted drug, Imatinib has achieved great success in the treatment of CML. Nevertheless, inevitable drug resistance of Imatinib has occurred frequently in clinical due to the several mutations in the BCR-ABL kinase. Subsequently, the second-generation of tyrosine kinase inhibitors (TKIs) against BCR-ABL was developed to address the mutants of Imatinib resistance, except T315I. To date, the third-generation of TKIs targeting T315I has been developed for improving the selectivity and safety. Notably, the first allosteric inhibitor has been in market which could overcome the mutations in ATP binding site effectively. Meanwhile, some advanced technology, such as proteolysis-targeting chimeras (PROTAC) based on different E3 ligand, are highly expected to overcome the drug resistance by selectively degrading the targeted proteins. In this review, we summarized the current research progress of inhibitors and degraders targeting BCR-ABL for the treatment of CML.
摘要：
慢性粒细胞白血病(CML)是造血系统的恶性疾病,其致病蛋白BCR-ABL,严重危及患者生命.作为靶向药物的里程碑，伊马替尼在治疗CML方面取得了巨大成功。然而，由于BCR-ABL激酶的多个突变,临床上经常发生伊马替尼不可避免的耐药.随后，针对BCR-ABL的第二代酪氨酸激酶抑制剂（TKIs）被开发用于解决伊马替尼耐药的突变体，除了T315I.迄今为止,已经开发了针对T315I的第三代TKIs,用于提高选择性和安全性.值得注意的是,第一种变构抑制剂已经上市,可以有效克服ATP结合位点的突变.同时,一些先进的技术，例如基于不同E3配体的蛋白水解靶向嵌合体（PROTAC），高度期望通过选择性降解目标蛋白质来克服耐药性。在这次审查中,本文就目前针对BCR-ABL的抑制剂和降解剂治疗CML的研究进展作一综述。
