BCR-ABL Inhibitors in the Targeted Therapy of Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a malignant disease of the hematopoietic system with a key pathogenic protein BCR-ABL, which seriously threatens the lives of patients. The first drug whose action is based on the inhibition of the hybrid tyrosine kinase BCR-ABL, the gene of which is located on the “Philadelphia chromosome,” was imatinib. Imatinib therapy turned out to be quite successful: patients with CML achieved a complete cytogenic response 2 years after the start of treatment and a state of stable longterm remission. However, the inevitable resistance to imatinib, which occurs in clinical settings due to mutations in the BCR-ABL kinase, gave impetus to the development of new specific drugs, such as dasatinib, nilotinib, bosutinib, and ponatinib. Currently, the pharmaceutical market offers the second and third generations of BCR-ABL tyrosine kinase inhibitors designed to combat mutant BCR-ABL and possessing better selectivity. It is noteworthy, the first allosteric inhibitor capable effectively overcome ATP binding site mutations has appeared on the market. In recent years, proteolysis-targeting chimeras (PROTAC) based on another E3 ligase ligand have been introduced, as a result they are able to overcome drug resistance through selective degradation of target proteins. Data on inhibitors that have received approved drug status for the treatment of CML are presented. Promising directions for developing novel BCR-ABL inhibitors are indicated. The relevance of this research direction is confirmed by the emergence of a significant number of new publications on this topic.