Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Hangzhou Chinese Academy of Sciences-Hangzhou Medical College Advanced Medical Technology Institute, Zhejiang, China.
Eur J Med Chem. 2022 Aug 5;238:114442. doi: 10.1016/j.ejmech.2022.114442. Epub 2022 May 6.
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.
慢性髓性白血病（CML）是一种造血系统的恶性疾病，其关键致病蛋白名为 BCR-ABL，严重威胁着患者的生命。伊马替尼作为靶向药物的一个里程碑，在 CML 的治疗中取得了巨大的成功。然而，由于 BCR-ABL 激酶的几个突变，伊马替尼不可避免地经常发生耐药性。随后，针对 BCR-ABL 的第二代酪氨酸激酶抑制剂（TKI）被开发出来，以解决伊马替尼耐药的突变体，除了 T315I。迄今为止，已经开发出针对 T315I 的第三代 TKI，以提高选择性和安全性。值得注意的是，第一个别构抑制剂已经上市，能够有效地克服 ATP 结合位点的突变。同时，一些先进的技术，如基于不同 E3 配体的蛋白酶体靶向嵌合体（PROTAC），有望通过选择性降解靶向蛋白来克服耐药性。在这篇综述中，我们总结了针对 BCR-ABL 的抑制剂和降解剂在治疗 CML 方面的最新研究进展。
Zotero 插件