BCR-ABL tyrosine kinase inhibitors

What are BCR-ABL tyrosine kinase inhibitors?

BCR-ABL tyrosine kinase inhibitors inhibit the enzyme BCR-ABL tyrosine kinase, which is important in the pathogenesis of chronic myelogenous leukemia (CML).

Chronic myelogenous leukemia occurs due a single genetic abnormality, known as the Philadelphia chromosome.

During the translocation when the Philadelphia chromosome is created, a fusion gene called BCR-ABL gene is formed. The BCR-ABL gene encodes for the BCR-ABL tyrosine kinase. The BCR-ABL positive cells in chronic myelogenous leukemia have increased proliferation and resistance to cell death.

BCR-ABL tyrosine kinase inhibitors are used to treat chronic myelogenous leukemia.

In all, dasatinib is smaller than imatinib and makes fewer interactions, and yet, it is a more potent inhibitor of Bcr-Abl. It has been suggested that the increase in binding affinity of dasatinib over imatinib may derive from an ability to recognize multiple states of Bcr-Abl.

The available BCR-ABL1 inhibitors are ATP competitors and have different binding properties. Imatinib, nilotinib, and ponatinib have stronger binding affinity to the inactive protein conformation, whereas dasatinib and bosutinib can bind both the active and inactive conformations.

Four of these drugs, nilotinib, dasatinib, bosutinib and ponatinib are approved for the treatment of imatinib-resistant or intolerant CML. The first-line data for these compounds are encouraging and suggest that some or all of them may replace imatinib as a frontline standard TKI in the future.