College of Pharmaceutical Science, Zhejiang University of Technology, and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, P.R. China.
Curr Med Chem. 2022;29(17):3050-3078. doi: 10.2174/0929867328666211012093423.
Tyrosine kinases expressed by BCR-ABL fusion genes can cause changes in cell proliferation, adhesion, and survival properties, which are the main causes of chronic myelogenous leukemia (CML). Inhibiting the activity of BCR-ABL tyrosine kinase has become one of the effective methods for the treatment of chronic myelogenous leukemia. Initially, imatinib was the first small molecule of BCR-ABL tyrosine kinases inhibitors (TKIs) for the effective treatment of chronic myelogenous leukemia. Later, due to the emergence of various BCR-ABL mutations, especially T315I mutation, imatinib developed strong resistance. The second-generation kinase inhibitors dasatinib and nilotinib were able to overcome most of the mutation resistance but not T315I mutations. Therefore, in order to further overcome the problem of drug resistance, new types of KTIs such as flumatinib and radotinib have been developed, providing more options for clinical treatment. Some new drugs have entered clinical trials. In this review, two new BCRABL inhibitors (flumatinib and radotinib) and five new BCR-ABL inhibitors have been introduced into the clinical market in recent years. We reviewed their research status, synthesis methods, and clinical applications.
BCR-ABL 融合基因表达的酪氨酸激酶可引起细胞增殖、黏附和存活特性的改变，这是慢性髓性白血病（CML）的主要原因。抑制 BCR-ABL 酪氨酸激酶的活性已成为治疗慢性髓性白血病的有效方法之一。最初，伊马替尼是第一个用于有效治疗慢性髓性白血病的 BCR-ABL 酪氨酸激酶抑制剂（TKI）小分子药物。后来，由于出现了各种 BCR-ABL 突变，尤其是 T315I 突变，伊马替尼产生了很强的耐药性。第二代激酶抑制剂达沙替尼和尼洛替尼能够克服大多数突变耐药性，但不能克服 T315I 突变。因此，为了进一步克服耐药问题，已经开发了新型 KTIs，如氟马替尼和拉多替尼，为临床治疗提供了更多选择。一些新药已进入临床试验。本综述介绍了近年来进入临床市场的两种新型 BCR-ABL 抑制剂（氟马替尼和拉多替尼）和五种新型 BCR-ABL 抑制剂，综述了它们的研究现状、合成方法和临床应用。
