Research Status, Synthesis and Clinical Application of Recently Marketed and Clinical BCR-ABL Inhibitors.

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.