Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

STI-571 (imatinib, Gleevec, Glivec, CGP 57148) is an inhibitor of the Abl group of protein-tyrosine kinases. One of these enzymes, the Bcr-Abl oncoprotein, results from the fusion of the BCR and ABL genes that result from the reciprocal chromosomal translocation that forms the Philadelphia chromosome. The Philadelphia chromosome occurs in 95% of people with chronic myeloid leukemia. ABL is the cellular homologue of the oncogene found in murine Abelson leukemia virus, and BCR refers to breakpoint cluster region. The Bcr-Abl oncoprotein exhibits elevated protein-tyrosine kinase activity, which is strongly implicated in the mechanism of development of chronic myeloid leukemia. STI-571 is effective in the treatment of the stable phase of chronic myeloid leukemia. The c-Abl protein kinase domain exists in an active and inactive conformation. STI-571 binds only to the inactive state of the enzyme as shown by X-ray crystallography. The drug binds to a portion of the ATP-binding site and extends from there into adjacent hydrophobic regions. STI-571 is a competitive inhibitor of Abl kinase with respect to ATP. Resistance to STI-571 is often the result of mutations in residues of the Bcr-Abl kinase that ordinarily bind to the drug. Inhibition of target protein kinases represents an emerging therapeutic strategy for the treatment of cancer.
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PMID:STI-571: an anticancer protein-tyrosine kinase inhibitor. 1367 30

Gastrointestinal stromal tumours (GISTs) are rare gastro-intestinal, mesenchymal tumours characterized by the expression of a receptor with tyrosine kinase activity called c-kit. A new drug, Imatinib, is a potent inhibitor of a subgroup of the tyrosine kinase family comprising BCR-ABL, platelet-derived growth factor, and c-kit. Imatinib represents the first systemic treatment with a clinical effect on patients with metastatic or unresectable GISTs, which are known to be resistant to chemo and radiotherapy. In the first phase I and II studies confirmed partial responses were seen in 53% and 59% of the patients respectively.
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PMID:[Imatinib--a breakthrough in the treatment of gastrointestinal stromal tumors (GIST)]. 1453 49

Inhibition of BCR-ABL tyrosine kinase activity has shown to be essential for the treatment of chronic myelogenous leukemia (CML). However, drug resistance has quickly arisen in recent clinical trials for STI571 (Gleevec), which is the first approved drug of CML by inhibiting ABL tyrosine kinase. It is desirable to develop new types of ABL tyrosine kinase inhibitors that may overcome this drug resistance problem. Here we present the discovery of novel inhibitors targeted at the catalytic domain of ABL tyrosine kinase by using three-dimensional database searching techniques. From a database containing 200,000 commercially available compounds, the top 1000 compounds with the best DOCK energy score were selected and subjected to structural diversity and drug likeness analysis, 15 compounds were submitted for biological assay. Eight out of the 15 showed inhibitory activity against K562 cells with IC(50) value ranging from 10 to 200 microM. Two promising compounds showed inhibition in further ABL tyrosine phosphorylation assay. It is anticipated that those two compounds can serve as lead compounds for further drug design and optimization.
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PMID:Identification of novel inhibitors of BCR-ABL tyrosine kinase via virtual screening. 1455 60

Imatinib mesylate (STI571, Glivec), a 2-phenylaminopyrimidine small-molecule ATP competitor-type kinase inhibitor, proved to be active in Philadelphia-positive leukemias. Resistance toward imatinib develops frequently in advanced-stage Philadelphia-positive leukemia, and is even observed in chronic-phase chronic myelogenous leukemia. Point mutations within the BCR-ABL kinase domain emerged as a major mechanism of resistance toward imatinib. Mutations occur at positions that determine specific contacts of imatinib to the ATP-binding site. We aimed to examine whether pyrido-pyrimidine-type kinase inhibitors were capable of inhibiting both wild-type and mutant forms of BCR-ABL. We screened 13 different pyrido-pyrimidine with cells expressing wild-type and mutant BCR-ABL. All of the substances specifically suppressed the Bcr-Abl dependent phenotype and inhibited Bcr-Abl kinase activity with higher potency than imatinib. Two of the most active compounds were PD166326 and SKI DV-M016. Interestingly, these compounds suppressed the activation loop mutant Bcr-Abl H396P as effectively as wild-type Bcr-Abl. In addition, nucleotide-binding loop mutations (Y253H, E255K, and E255V) were selectively and potently inhibited. In contrast, T315I, a mutant located at a position that makes a direct contact with imatinib, was not affected. This observation is consistent with the hypothesis that unlike imatinib, pyrido-pyrimidine inhibitors bind Bcr-Abl regardless of the conformation of the activation loop. We conclude that pyrido-pyrimidine-type kinase inhibitors are active against different frequently observed kinase domain mutations of BCR-ABL that cause resistance toward imatinib. Resistance as a consequence of selection of mutant BCR-ABL by imatinib may be overcome using second-generation kinase inhibitors because of their higher potency and their ability to bind Bcr-Abl irrespective of the conformation of the activation loop.
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PMID:Inhibition of wild-type and mutant Bcr-Abl by pyrido-pyrimidine-type small molecule kinase inhibitors. 1455 29

Imatinib is a tyrosine-kinase inhibitor that binds to ABL proteins and induces cytogenetic remissions in patients with chronic myeloid leukemia (CML). In these patients measuring response by molecular techniques is clearly required. We determined the cytogenetic and molecular response (CgR, MR) to imatinib in 191 patients with late chronic-phase Philadelphia-positive (Ph+) CML, previously treated with interferon alpha. MR was assessed with real-time quantitative (TaqMan) reverse transcription-polymerase chain reaction and was expressed as the ratio between BCR/ABL and beta 2-microglobulin x 100, the lowest level of detectability of the method being 0.00001. A complete CgR (CCgR) was achieved in 85 (44%) of 191 patients and was maintained for 2 years in 67 (79%) of 85 patients. A reduction of the transcript level of more than 2 logs was achieved in all but 9 patients with CCgR versus none of 23 with partial CgR. In the CCgRs the median value of the MR was 0.0008 after 12 months and 0.0001 after 24 months, with the transcript level undetectable in 22 cases. We conclude that in CCgRs the degree of MR may vary from 2 to more than 4 logs, and that there is a progressive decrease of transcript level by time. Only 1 of 22 negative cases has had a relapse as yet.
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PMID:Molecular response to imatinib in late chronic-phase chronic myeloid leukemia. 1464 9

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the BCR-ABL fusion protein in CML, and was superior to IFN-alpha plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in BCR-ABL-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular BCR-ABL protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-TRANS-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-alpha (PML/RARalpha) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.
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PMID:Apoptosis induced by molecular targeting therapy in hematological malignancies. 1464 49

Decreased Type 1 cytokine production has been observed in T cells of patients with untreated chronic myeloid leukemia (CML). The important role of T cells and T-cell cytokines in the long-term control of CML is well established, for example in allogeneic stem-cell graft recipients. This study examined whether or not molecularly targeted therapy with imatinib, an inhibitor of the BCR-ABL tyrosine kinase, improved endogenous T-cell function in patients resistant to or intolerant of previous IFN-alpha therapy. Intracellular cytokine staining and detection by flow cytometry was used to analyze the expression of the T1 cytokine IFN-gamma in T cells. To secure independence from changes in white blood cell counts during treatment, a constant number of T cells was purified from the peripheral blood before analysis of the proportion of IFN-gamma synthesizing T cells. Twenty-nine patients with CML were tested before and after a median follow-up of 3 month on imatinib. In addition, late follow-up (past the median time to best cytogenetic response) of 15 patients were obtained Twenty-nine age- and gender-matched individuals were used as healthy controls. The frequency of IFN-gamma producing T cells in CML patients resistant to or intolerant to previous IFN-alpha therapy was lower than in healthy individuals (p=0.0181, Mann-Whitney test). Imatinib therapy led to a significant increase over pre-treatment values (p<0.0001, Mann-Whitney test). Late follow-up indicated that the increase was sustained in patients not in major cytogenetic response. In contrast, in major responders levels returned towards values comparable to healthy individuals. In conclusion, treatment with imatinib achieves a significant increase in Type 1 (IFN-gamma) cytokine-producing T cells in patients with CML. This is consistent with the view that enhanced T-cell function is achievable in patients with CML, even in the absence of allo-mechanisms.
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PMID:Increased IFN-gamma synthesis by T cells from patients on imatinib therapy for chronic myeloid leukemia. 1466 54

Imatinib (Glivec), STI571) is an intracellular acting drug that demonstrates high activity against BCR-ABL-positive chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL). However, many patients, especially with advanced disease, develop drug resistance. Here, we show by a novel high-performance liquid chromatography-based method that intracellular levels of imatinib decrease in P-glycoprotein (Pgp)-positive leukemic cells. In a model of K562 cells with gradually increasing Pgp expression, a Pgp-dependent decline of intracellular imatinib levels was observed. Decreased imatinib levels were associated with a retained phosphorylation pattern of the Bcr-Abl target Crkl and loss of effect of imatinib on cellular proliferation and apoptosis. The modulation of Pgp by cyclosporin A (CSA) readily restored imatinib cytotoxicity in these cells. Finally, we provide first data showing a biological effect of Pgp modulation in the imatinib treatment of a patient with BCR-ABL-positive ALL. MDR1 overexpression must therefore be considered as an important clinical mechanism in the diversity of resistance development to imatinib treatment.
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PMID:P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. 1472 52

Gastrointestinal stromal tumours (GISTs), the most common mesenchymal tumours of the digestive tract, are largely resistant to chemo- and radiotherapy. They are currently defined by their overexpression of the KIT receptor tyrosine kinase (CD117), a member of the family of receptor tyrosine kinases (RTKs), and exhibit KIT mutations in more than 85% of cases. Additionally, in more than one-third of KIT wild-type GISTs, mutations of platelet-derived growth factor receptor alpha (PDGF-R alpha), which also belongs to the family of RTKs, were recently found. Since these data indicate that uncontrolled RTK signalling may be implicated in the pathogenesis of GISTs, RTKs and the activated downstream signalling cascades are attractive targets in the therapy of these tumours. Imatinib is a small-molecule inhibitor that selectively blocks the activity of the PDGF-R, ABL and KIT receptor tyrosine kinases by competitive binding to the adenosine triphosphate binding site of their catalytic domains. We herein review the molecular pathological, preclinical and clinical data that identify imatinib as a valuable new agent in the treatment of GISTs.
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PMID:Gastrointestinal stromal tumours and their response to treatment with the tyrosine kinase inhibitor imatinib. 1473 60

Imatinib, a specific inhibitor of the Abl, Kit and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, is effective in all phases of chronic myelogenous leukemia. While responses in chronic phase are usually durable, resistance frequently develops in patients with advanced disease after an initial response. Several mechanisms of resistance have been demonstrated in vivo, including mutations in the BCR-ABL kinase domain and amplification of the BCR-ABL gene. We analyzed cytogenetics and screened for mutations of the BCR-ABL kinase domain as well as the activation loops of KIT and PDGFRA and B in 49 patients with CML or Ph-positive acute lymphoblastic leukemia with resistance to imatinib. Mutations in the kinase domain of BCR-ABL were detected in 51.6% of patients with secondary resistance but not in patients with primary resistance. Three of these mutations have not been described before (T315D, F359D and D276G). By contrast, KIT and PDGFRA and B were consistently wildtype. Clonal evolution prior to imatinib was present in 68.8% of patients with primary resistance and in 45.5% with secondary resistance. Additional cytogenetic aberrations developed in 18.2% of patients at the time of relapse. Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of KIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.
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PMID:High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib. 1474 31


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