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)

Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia. Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).
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PMID:Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. 1847 70

At the time of writing, there are seven marketed kinase inhibitor drugs. The first kinase inhibitor, imatinib mesilate (Gleevec, Novartis), came to market in 2001, an inhibitor of the breakpoint cluster region (BCR)/Abelson murine leukemia oncogene homolog (ABL) fusion, platelet-derived growth factor (PDGF) receptor, and c-kit kinases. The most recent kinase inhibitor to come to market, disatinib (Sprycel, Bristol-Myers Squibb), acts on c-SRC, ABL and Bruton's tyrosine kinase. To date, kinase inhibitor drugs are approved for oncology and demonstrate that it is possible to develop compounds with relative selectivity for the target kinase against the broader kinome. However, the use of kinase inhibitors in chronic inflammatory and immunologic diseases may require greater selectivity for the target kinase. This review addresses the opportunities and challenges of kinase inhibition as a therapeutic approach in chronic immune and inflammatory disease.
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PMID:Kinase inhibitors as drugs for chronic inflammatory and immunological diseases: progress and challenges. 1855 56

We have previously shown that imatinib uptake into chronic myeloid leukemia (CML) cells is dependent on human organic cation transporter 1 (hOCT1; SLC22A1), and that low hOCT1 expression is an important determinant of clinical outcome to imatinib treatment. We hypothesized that dasatinib might be transported differently than imatinib, possibly accounting for its favorable effects in imatinib-resistant patients. (14)C-dasatinib uptake was greater in KCL22-transfected cells with pcDNA3-hOCT1 plasmid (high hOCT1-expressing cells) than in control cells (P = .02). However, hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells, in contrast to their block on imatinib uptake. Dasa-tinib decreased the level of phosphorylated CrkL to 49.9% in control and 40.3% in high hOCT1-expressing cells. Dasa-tinib efflux was investigated in confluent ABCB1-transfected MDCKII cell monolayers. Both dasatinib and imatinib were transported from the basal to the apical layer, indicating that they were transported by ABCB1, which was confirmed using the ABCB1 inhibitor PSC833 (P = .001 and P < .001, respectively). Compared with imatinib, dasatinib achieved superior intracellular levels and BCR-ABL suppression even in cells with low or blocked hOCT1. Efflux of dasatinib and imatinib appear similar via ABCB1. Dasatinib may therefore offer an advantage over imatinib in patients with low hOCT1 expression.
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PMID:Effective dasatinib uptake may occur without human organic cation transporter 1 (hOCT1): implications for the treatment of imatinib-resistant chronic myeloid leukemia. 1866 73

Dasatinib is an inhibitor of BCR-ABL and SRC-family kinases for patients with imatinib-resistant or -intolerant chronic myelogenous leukemia (CML). In this international phase II trial, dasatinib was administered orally (70 mg twice daily) to patients with myeloid blast phase (MBP, n=109) or lymphoid blast phase (LBP, n=48) CML. After a minimum follow-up of 12 months (range 0.03-20.7 months), major hematologic responses were induced in 34% (MBP-CML) and 35% (LBP-CML) of patients. Major cytogenetic responses were attained in 33% (MBP-CML) and 52% (LBP-CML) of patients and complete cytogenetic responses were attained in 26 and 46%, respectively. Median progression-free survival was 6.7 (MBP-CML) and 3.0 (LBP-CML) months. Median overall survival was 11.8 (MBP-CML) and 5.3 (LBP-CML) months. Overall, dasatinib had acceptable tolerability. Fluid retention events were more frequent in the MBP-CML than the LBP-CML cohort: pleural effusion occurred in 36 and 13% (all grades) and 15 and 6% (grades 3/4), respectively. Other non-hematologic side effects were primarily grade 1/2; grade 3/4 events were recorded in <or=6% of patients, except febrile neutropenia (15%). Cytopenias were noted in the majority of patients, and were manageable with dose interruptions/reductions. Dasatinib is associated with a promising rate of response in this high-risk population.
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PMID:Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. 1875 32

Imatinib is widely recognized as the standard of care in the first-line treatment of chronic myeloid leukemia (CML); however, resistance can limit its long-term benefits. Early identification of the loss of response to imatinib is therefore important for the optimal management of patients with this type of leukemia. Cytogenetic and molecular responses during the first 12 months of treatment have been shown to predict future responses (complete cytogenetic response and major molecular response) and reduce disease progression. The degree of early reduction in BCR-ABL levels after commencing imatinib therapy is a good indicator of subsequent response. Monitoring for kinase domain mutations should also be considered in patients with suboptimal response or in those who demonstrate resistance. Modification of the treatment strategy is required if there is a loss of response. Dasatinib and nilotinib are the most extensively studied second-generation BCR-ABL tyrosine kinase inhibitors, and are currently approved for treating patients following imatinib failure.
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PMID:What is imatinib-resistant chronic myeloid leukemia? Identifying and managing loss of response. 1882 90

Imatinib was the first BCR-ABL-targeted agent approved for the treatment of patients with chronic myeloid leukemia (CML) and confers significant benefit for most patients; however, a substantial number of patients are either initially refractory or develop resistance. Point mutations within the ABL kinase domain of the BCR-ABL fusion protein are a major underlying cause of resistance. Of the known imatinib-resistant mutations, the most frequently occurring involve the ATP-binding loop (P-loop). In vitro evidence has suggested that these mutations are more oncogenic with respect to other mutations and wild type BCR-ABL. Dasatinib and nilotinib have been approved for second-line treatment of patients with CML who demonstrate resistance (or intolerance) to imatinib. Both agents have marked activity in patients resistant to imatinib; however, they have differential activity against certain mutations, including those of the P-loop. Data from clinical trials suggest that dasatinib may be more effective vs. nilotinib for treating patients harboring P-loop mutations. Other mutations that are differentially sensitive to the second-line tyrosine kinase inhibitors (TKIs) include F317L and F359I/V, which are more sensitive to nilotinib and dasatinib, respectively. P-loop status in patients with CML and the potency of TKIs against P-loop mutations are key determinants for prognosis and response to treatment. This communication reviews the clinical importance of P-loop mutations and the efficacy of the currently available TKIs against them.
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PMID:P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia. 1882 13

The expressions of c-Src and focal adhesion kinase (FAK) were studied in 65 Chinese patients with hepatocellular carcinoma (HCC) by immunohistochemistry using rabbit monoclonal antibodies. Expressions of total Src, an active form of Src, and FAK were found in 44/65 (67.7%), 36/45 (55.4%), and 33/56 (58.9%) HCC cases, respectively. There was a good correlation between the expression of total Src, active form of Src, and FAK in these HCC cases (P < 0.001). Expression of Src was not correlated to any clinical parameters, cancer cell phenotypic markers, and pathologic features apart from a positive correlation with alpha-fetoprotein (P < 0.01). The expression of FAK was correlated with earlier onset and the expression of Ki-67 but not proliferating cell nuclear antigen (PCNA) in these HCC cases. Four liver-cancer-derived cell lines (three derived from HCC and one from hepatoblastoma) were then tested with inhibitors against Src. A small molecule, KX2-391, designed to target the substrate binding pocket of Src, was found to have more broad-spectrum activity and better potency than Dasatinib, an adenosine triphosphate (ATP)-competitive inhibitor in vitro. Our data indicates that Src and FAK expression are both elevated and active in Chinese patients with HCC and that Src may play a key role in supporting HCC progression. Src antagonism with specific inhibitors may be an attractive treatment paradigm for patients with HCC.
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PMID:Expression of Src and FAK in hepatocellular carcinoma and the effect of Src inhibitors on hepatocellular carcinoma in vitro. 1897 99

Src family kinases (SFK) are involved in regulating a multitude of biological processes, including cell adhesion, migration, proliferation, and survival, depending on the cellular context. Therefore, although SFKs are currently being investigated as potential targets for treatment strategies in various cancers, the biological responses to inhibition of SFK signaling in any given tumor type are not predictable. Dasatinib (BMS-354825) is a dual Src/Abl kinase inhibitor with potent antiproliferative activity against hematologic malignancies harboring activated BCR-ABL. In this study, we show that dasatinib blocks migration and invasion of human melanoma cells without affecting proliferation and survival. Moreover, dasatinib completely inhibits SFK kinase activity at low nanomolar concentrations in all eight human melanoma cell lines investigated. In addition, two known downstream targets of SFKs, focal adhesion kinase and Crk-associated substrate (p130(CAS)), are inhibited with similar concentrations and kinetics. Consistent with inhibition of these signaling pathways and invasion, dasatinib down-regulates expression of matrix metalloproteinase-9. We also provide evidence that dasatinib directly inhibits kinase activity of the EphA2 receptor tyrosine kinase, which is overexpressed and/or overactive in many solid tumors, including melanoma. Thus, SFKs and downstream signaling are implicated as having key roles in migration and invasion of melanoma cells.
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PMID:Inhibition of Src family kinases with dasatinib blocks migration and invasion of human melanoma cells. 1901 Aug 23

Recent advances in the molecular characterization of Philadelphia chromosome-negative (Ph-) leukemias and related myeloid disorders have provided a clear rationale for investigating novel targeted therapies. Dasatinib is a tyrosine kinase inhibitor with activity against BCR-ABL, platelet-derived growth factor receptors (PDGFRs), c- KIT, fibroblast growth factor receptors (FGFRs), SRC family kinases (SFKs), and EPHA receptors, all of which have been implicated in the pathogenesis of Ph- leukemias and myeloid disorders. This review presents emerging data on the preclinical and clinical activity of dasatinib in these diseases, which suggest that larger clinical studies are warranted.
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PMID:Preclinical and clinical experience with dasatinib in Philadelphia chromosome-negative leukemias and myeloid disorders. 1901 41

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between the long arms of the chromosomes 9 and 22 t(9;22)(q34;q11). This translocation creates two new genes, BCR-ABL on the 22q- (Ph chromosome) and the reciprocal ABL-BCR on 9q-. The BCR-ABL gene encodes for a 210-kD protein with deregulated tyrosine kinase (TK) activity, which is crucial for malignant transformation in CML. The recognition of the BCR-ABL gene and corresponding protein led to the synthesis of small-molecule drugs, designed to interfere with BCR-ABL tyrosine kinase activation by competitive binding at the ATP-binding site. The first tyrosine kinase inhibitor (TKI), introduced into clinical practice in 1998, was imatinib mesylate. Imatinib became the first choice drug in chronic phase CML, because of its high efficacy, low toxicity and ability to maintain durable hematological and cytogenetic responses. However, approximately 20-25% of patients initially treated with imatinib will need alternative therapy, due to drug resistance, which is often caused by the appearance of clones expressing mutant forms of BCR-ABL. Second-generation TKIs have provided new therapeutic option for the patients resistant to imatinib. Dasatinib is the first, second-generation TKI, approved in the US and European Union for the treatment of CML patients with imatinib resistance or intolerance. This drug is a dual SRC-ABL kinase inhibitor, active in most clinically relevant BCR-ABL mutations, except highly resistant T315I. Other second-generation TKIs include nilotinib, bosutinib and INNO 406. Apart from TKIs, the promising group of molecules is inhibitors of Aurora family of serine-threonine kinases. One of these molecules, MK0457, has entered clinical trials, and initial reports indicate that this compound could be active in disease associated with T315I mutation. Thus, wide spectrum of new agents, with different mode of action, is currently in clinical development for CML. It is likely that combination therapy will be the best therapeutic strategy in the future.
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PMID:Targeted drugs in chronic myeloid leukemia. 1907 51


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