Chronic myeloid leukemia (CML) is a myeloproliferative disease caused due to
translocation between chromosome 9 and 22 leading to a chimeric gene product known as Bcr-Abl.
Bcr-Abl fusion protein has constitutively activated Abl tyrosine kinase activity which is responsible for
the uncontrolled proliferation in CML The tyrosine kinase inhibitors (TKIs) such as Imatinib,
Dasatinib, and Nilotinib are the current first-line treatments approved by the United States Food and
Drug Administration (US FDA) for the treatment of the disease. Despite the spectacular progress made
over the decade with the TKIs, patients develop resistance to these TKIs. In such cases, stem cell
transplant therapy, which is limited by donor availability, is the only proven cure for the patients. This
highlights the need for the development of new strategies for CML treatment. The Bcr-Abl point mutations,
including the gatekeeper T315I mutations, are the principal cause for the development of resistance
to TKIs. However, other mechanisms are also involved in the failure of TKI therapy. This review
outlines the Bcr-Abl dependent and independent mechanism of TKIs resistance development and the
strategies used to overcome drug resistance, such as the development of ATP site and allosteric site inhibitors.
Binding mode and structural elements of Bcr-Abl inhibition are discussed with emphasis on
pathways involved in this complex disease to determine alternative strategies and combination therapies.
Keywords: ATP competitive inhibitor, allosteric inhibitor, Bcr-Abl, chronic myeloid leukaemia, drug resistance, T315I mutation,
tyrosine kinase inhibitor.
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