Imatinib: Basic Results
2017
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.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
113
References
1
Citations
NaN
KQI