BCR/ABL

In this example, structure-based design of inhibitors to the mutant enzyme may be undertaken using available X-ray structures and homology models. 

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Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

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. 

Gleevec (Imatinib, STI571) ATP-analogue BCR-ABL Cancer Clinic... 

LBH589, 17-AAG Chaperone inhibitor Hsp90/BCR-ABL Cancer Phase I... 

Imatinib (Gleevec) TKI Bcr-Abl, c-Kit, PDGFR, Lck Inhibition of kinase activity - ATP-competitive, binding to an inactive conformation CML ALL GIST DFSP MDS/MPD ASM HES/CEL... 

Though a large number of small molecule inhibitors against a variety of tyrosine kinases are being developed, the most advanced drugs can be roughly classified as (i) Bcr-Abl/Src family kinase inhibitors, (ii) ErbB inhibitors and (iii) broad spectrum TfCIs with an anti-angiogenic component. 

In chronic myelogenous leukemia (CML) as well as in a subset of acute lymphoblastic leukemia (ALL) Bcr-Abl, a fusion protein of c-Abl and the breakpoint cluster region (bcr), is expressed in the cytosol of leukemic cells. This fusion protein forms homo-oligomeric complexes that display elevated kinase activity and is the causative molecular abnormality in CML and certain ALL. The transforming effect of Bcr-Abl is mediated by numerous downstream signaling pathways, including protein kinase C (PKC), Ras-Raf-ERK MAPK, JAK-STAT (see below), and PI3-kinase pathways. 

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. 

BCR-ABL Codes for a nonreceptor tyrosine kinase Chronic myelogenous leukemia... 

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,... 

Tyrosine kinase inhibitor relatively specific for the tyrosine kinase coded for by the bcr-abl translocation in CML patients... 

The Philadelphia chromosome results in the formation of an abnormal fusion gene, BCR-ABL, that encodes an overly active tyrosine kinase. 

Gleevec ) is a tyrosine kinase inhibitor used as first-line therapy in the majority of patients with CML. As a potent tyrosine kinase inhibitor, imatinib inhibits phosphorylation of various proteins involved in cell proliferation. Imatinib works by binding to the ATP-binding pocket of BCR-ABL.7 The drug induces complete hematologic responses in more than 95% of patients and complete cytogenetic responses in about 80% of patients in chronic phase.8 Most patients have traces of the disease when measured by RT-PCR and are not cured of their disease. 

To monitor for the effectiveness of the HCT, monitor for symptoms and signs of the disease that is being treated by HCT. For example, the monitoring plan for a patient with CML would be to monitor disease response by PCR of the BCR-ABL transcript. The actual clinical outcome monitored, along with the frequency of monitoring, is based on the underlying disease. 

BCR-ABL tyrosine kinase Cancer Point mutation causes resistance to STI-571 compound 21... 

Fig. 7.2 Mutation of Thr315 (A) to lie (B) in BCR-ABL interferes with the binding of STI-571 (see color plates, p.XXXIII).

Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001 293 876-880. 

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