Imatinib used in CML acts by
Competitive inhibition _of ATP binding site of ABL kinase [Ref. Harrison 16thie p 4781 CML is characterized by the presence of a distinctive molecular abnormality namely philadelphia chromosome. Philadelphia chromosome in formed as a result of reciprocal translocation between long arm of chromosome 22 and chromosome 9 i.e. t (9 ; 22). ABL protooncogene from chromosome 9 is translocated to chromosome 22 where BCR is present and results in formation of BCR-ABL fusion chimeric gene. The drug imatinib mesylate is a BCR-ABL tyrosine kinase signal transduction inhibitor. This drug acts as a inhibitor of the ATP binding site on the protein and prevents its phosphorylation and thus its activity. An impoant point CML is caused by reciprocal translocation between BCR and ABL gene located on chromosome 9 and 22. Imatinib mesylate does not block this translocation i.e., BCR ABL translocation. - Instead, it blocks the constitutive abnormal tyrosine kinase, BCR-ABL that is created by the Philadelphia chromose (BCR-ABL). - The drug inhibits the proliferation and induces apoptosis in BCR-ABL positive cells. Also know Protein tyrosine kinase inhibitors Protein kinases are ubiquitous and critical components of signal transduction pathways that transmit information concerning extra cellular or cytoplasmic conditions to the nucleus, thereby influencing gene transcription and/or DNA synthesis. The protein kinases can be classified into three categories: (i) Tyrosine kinase (ii) Serine threonine kinase (iii) Kinases with activity for all three residues Abnormal activation of specific tyrosine kinase has been demonstrated in many human neoplasms. Thus they can be targeted in ceain cancer therapies. There currently are three small-molecular weight protein tyrosine kinase inhibitors that are FDA approved and many others are in clinical trials. i) Imatinib Imatinib has efficacy in diseases in which the ABL, KIT or PDGFR have dominant roles in driving the proliferation of the tumour. Thus, imatinib shows remarkable therapeutic benefits in patients with - CML (BCR-ABL) - GIST (KIT mutation positive) - CMML (EVT6-PDGFR) ii) Gefitinib The epidennal growth factor receptor (EGFR) belongs to the family of tyrosine kinase. Gefitinid is a specific inhibitor of the EGFR tyrosine kinase that competitively inhibits ATP binding. EGFR is overexpressed in non-small cell carcinoma of lung, thus Gefitinib has been approved for use in non-small cell carcinoma. iii) Erlotinib It is a human HERI/EGFR tyrosine kinase inhibitor. It is indicated for patients with locally advanced or metastatic non-small cell lung cancer.
inhibiting Bcr/abl translocation tyrosine kinase
Blocking the action of P-glycoprotein
Competitive inhibition of ATP binding site of Abl kinase
C-kit kinase inhibition