Abstract
Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the reciprocal translocation t(9;22), which leads to the production of the Philadelphia (Ph) chromosome, encoding BCR-ABL tyrosine kinase. BCR-ABL is constitutively activated and induces malignant transformation of primitive hematopoietic cells. Imatinib mesylate (also known as STI571, GLEEVEC, or GLIVEC) is a 2-phenylaminopyrimidine derivative that received FDA approval as the first mechanism-based targeted small-molecule protein kinase inhibitor in 2001. Imatinib acts as an ATP-competitive inhibitor via interaction with the ABL kinase domain that results in the formation of six hydrogen bonds and through direct inhibition of BCR-ABL kinase activity. It inhibits BCR-ABL’s ability to transfer phosphate groups to tyrosine residues on the substrate, which blocks the subsequent activation of the proliferative signals. Although imatinib is an effective frontline therapy that has provided a remarkable success in the treatment of CML, the resistance to the inhibitor is still an obstacle. Quiescent leukemic stem cells are unresponsive to imatinib. BCR-ABL-dependent and BCR-ABL-independent mechanisms of drug resistance have been reported. To overcome imatinib resistance, the pharmacological targeting of key pathways alone or in combination with tyrosine kinase inhibitor (TKI) is being investigated.
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Tsukahara, F., Maru, Y. (2017). Imatinib: Basic Results. In: Ueda, T. (eds) Chemotherapy for Leukemia. Springer, Singapore. https://doi.org/10.1007/978-981-10-3332-2_2
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