Kinase imatinib

Abstract The hallmark of chronic myelogenous leukemia (CML) is the expression of Bcr-Abl, a constitutively active form of the Abl tyrosine kinase. Imatinib, a 2-phenylamino-pyrimidine Bcr-Abl inhibitor developed by Novartis and marketed under the tradename of Gleevec (Glivec), is highly effective in treating CML patients with early stage disease. However, patients with advanced disease often become resistant to imatinib. The predominant form of this resistance is the development of mutations in the Bcr-Abl protein. These point mutations can be amino acid residues that make direct contact with imatinib or residues that do not allow Bcr-Abl to adopt the inactive conformation. Since imatinib can only bind to the inactive conformation of the protein, both types of mutations prevent this inhibitor from binding. Several approaches have been taken to identify additional... 

Figure 20.4 X-ray structures of the binding sites of the Abl kinase/imatinib and cytochrome P450 3A4 /erythromycin complexes (PDB Protein Data Bank). The amino acids located within 4A of ligands are depicted. The hydrogen bonding interactions are shown by dashed lines, and the amino acids participating in hydrogen-bonding interactions are labeled in bold. The images were produced with Pymol (DeLano Scientific LLC). See color plates.

Subsequent investigations of this chemistry were focused on preparing analogs of CGP 60474, 94 [34], This compound was found to be a protein kinase C (PKC) inhibitor. PKC plays a critical role in signal transduction cascades that are involved in cellular proliferation and differentiation. CGP 60474 exhibits selectivity when compared to serine/threonine and tyrosine kinases. Imatinib 95 (Glivec) is a tyrosine kinase inhibitor currently on the market for chronic myeloid leukemia (CML). 

A number of anticancer drugs have been developed that specifically target kinases known to be oncogenic. The first drug in this area is imatinib mesylate, which targets... 

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. 

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... 

Note that application in the particular indications is usually restricted either to patients expressing the target (e.g. trastuzumab, cetuximab, lapatinib, imatinib) and/or after failure of prior therapies (e.g. cetuximab, erlotinib, lapatinib, sutinib, dasatinib). Furthermore, for cancer treatment most tyrosine kinase inhibitors are applied in combination with conventional chemotherapeutic drugs, such as fluorouracil, taxanes, platin-based regimens, anthracylines and irinotecan or radiotherapy. 

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,... 

Imatinib is a tyrosine kinase inhibitor that produces high complete response rates and is first-line treatment for chronic myelogenous leukemia (CML). 

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. 

Imatinib Mesylate (Gleevec) Tyrosine kinase inhibitor bcr-abl, c-kit Chronic myelogenous leukemia Hematologic and cytogenetic response rate. Phase III GIST ... 

Imatinib mesylate (Gleevec, Novartis) tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (refer to Exhibit 7.3)... 

Imatinib mesylate (Gleevec, Novartis Glivec in countries other than the United States) is a drug for the treatment of chronic myeloid leukemia (CML). CML is a result of a chromosomal problem and gives rise to high levels of white blood cells. An enzyme called BCR-ABL is involved. The BCR-ABL gene encodes a protein with elevated tyrosine kinase activity (see Exhibit 7.3). 

Imatinib mesylate is a tyrosine kinase inhibitor (see Chapter 2 on receptors). It is used to block the growth of white blood cells. 

Since the enzymatic activity of the protein encoded by the BCR-ABL gene is responsible for the cancer, it is logical to search for ways to tnm off that activity. The most straightforward way to tnm off the activity of an enzyme is to discover an inhibitor of the enzyme. We need a molecnle that specifically binds to the enzyme and tnms it off. That is precisely what imatinib does it specifically binds to the tyrosine kinase encoded by the BCR-ABL gene and abolishes its activity. In effect, imatinib converts the cancer cells of CML into the functional eqnivalent of normal cells normal cells do not have the enzyme and the imatinib-treated CML cells do not... 

Kopt Ta M, Falinski R, Nowicki MO et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 2006 108 319-327. 

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