Bcr-Abl-tyrosine kinase inhibitor

BCR-ABL tyrosine kinase that is essential for malignant transformation. Cytogenetic responses to IFN-a therapy were seen in 30-40% of the treated patients with complete responses in about 10%. Long term survival can therefore be expected in these patients. In 2000, the BCR-ABL tyrosine kinase inhibitor Imatinib has been introduced for CML therapy and meanwhile has proven more efficient than IFN-a therapy. 

Tanaka C et al (2010) Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib. Clin Pharmacol Ther 87 197-203... 

Figure 2.19 The lead structure 67 is a protein kinase C (PKC) inhibitor prototype. Whereas the optimized analog 68 is a strong PKC inhibitor, amides 69 also inhibit tyrosine kinases like the bcr-abl kinase. Introduction of a methyl group, to form 70, abolishes the PKC activity. The optimized analog imatinib 71 (Gleevec , Glivec , Novartis) is a highly selective bcr-abl tyrosine kinase inhibitor.

Schiffer CA (2007) BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med 357 258-265... 

Peng H, Huang N, Qi J, Xie P, Xn C, Wang J, Yang C. Identification of novel inhibitors of BCR-ABL tyrosine kinase via virtnal screening. Bioorg Med Chem Lett 2003 13 3693-9. 

The proportion of ALL in patients older than age 60 years constitutes between 16% and 31% of all adult leukemias. Treatment of adults largely has followed the conventional chemotherapeutic regimes used in childhood ALL. However, the intensification regimens common in childhood are not suitable for this population because of their associated toxic-ities in older patients. The adverse prognostic factor, the Philadelphia chromosome, occurs in 15% to 30% of adults and thus is more common in the over 60 age group.17 Based on the experience achieved in CML, the use of imatinib, a potent inhibitor of the Ph+-associated BCR-ABL tyrosine kinase, is becoming a common practice for these older adults. Results show that the combination of imatinib with conventional chemotherapy has improved remission rates compared with the use of conventional chemotherapy alone,... 

Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capde-ville R, Talpaz M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome N. Engl J Med 2001 344 1084-1086. 

Imatinib mesylate was the first tyrosine kinase inhibitor to be approved for treatment of cancer (see Table 124—18). It inhibits deregulated bcr-abl tyrosine kinase, the molecular abnormality in patients with chronic myelogenous leukemia that results from the characteristic Philadelphia chromosome translocation. The deregulated tyrosine kinase constantly drives leukemic cell proliferation. Imatinib inhibits cell proliferation and induces apoptosis in the Philadelphia chromosome-positive cells. It is relatively, but not completely, selective for these cells. °°... 

The prototype molecularly targeted therapeutic agent is imatinib, an inhibitor of the Bcr-Abl tyrosine kinase. This oncogenic kinase is produced by translocation of the Bcr locus on chromosome 9 to the c-Abl tyrosine kinase on chromosome 11, termed the Philadelphia chromosome because of its discovery in 1960 at the University of Pennsylvania School of Medicine by Peter Nowell and David Hungerford from the Institute for Cancer Research [9]. It was later demonstrated in 1973 by Janet Rowley that the Philadelphia translocation was responsible for a specific form of leukemia, chronic myelogenous leukemia (CML) [10], In 2001, imatinib was approved for treatment of CML patients, and produced remarkable results with more than 92% patients achieving 14-month progression-free survival on imatinib as a monotherapy. 

STI 571 <322> (<322>, a phenylaminopyrimidine derivative, a potent inhibitor of the Abl tyrosine kinase, PDGFR kinases and c-Kit tyrosine kinases [705] <322> designed to inhibit ABL and BCR-ABL tyrosine kinases, inhibition through competitive ATP-binding pocket interactions [706] <322> use un second-line therapy of small-cell lung cancer, inhibits c-kit kinase, resulting in an metabolic change of tumor cells [706]) [705, 706]... 

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