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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small molecule inhibitors belonging to the pyrido[2,3-d]pyrimidine class of compounds were developed as antagonists of protein tyrosine kinases implicated in cancer progression. Derivatives from this compound class are effective against most of the imatinib mesylate-resistant BCR-ABL mutants isolated from advanced chronic myeloid leukemia patients. Here, we established an efficient proteomics method employing an immobilized pyrido[2,3-d]pyrimidine ligand as an affinity probe and identified more than 30 human protein kinases affected by this class of compounds. Remarkably, in vitro kinase assays revealed that the serine/threonine kinases Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK) and p38alpha were among the most potently inhibited kinase targets. Thus, pyrido[2,3-d]pyrimidines did not discriminate between tyrosine and serine/threonine kinases. Instead, we found that these inhibitors are quite selective for protein kinases possessing a conserved small amino acid residue such as threonine at a critical site of the ATP binding pocket. We further demonstrated inhibition of both p38 and RICK kinase activities in intact cells upon pyrido[2,3-d]pyrimidine inhibitor treatment. Moreover, the established functions of these two kinases as signal transducers of inflammatory responses could be correlated with a potent in vivo inhibition of cytokine production by a pyrido[2,3-d]pyrimidine compound. Thus, our data demonstrate the utility of proteomic methods employing immobilized kinase inhibitors for identifying new targets linked to previously unrecognized therapeutic applications.
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PMID:Chemical proteomic analysis reveals alternative modes of action for pyrido[2,3-d]pyrimidine kinase inhibitors. 1547 68

Selective inhibition of protein tyrosine kinases is gaining importance as an effective therapeutic approach for the treatment of a wide range of human cancers. However, as extensively documented for the BCR-ABL oncogene in imatinib-treated leukaemia patients, clinical resistance caused by mutations in the targeted oncogene has been observed. Here, we look at how structural and mechanistic insights from imatinib-insensitive Bcr-Abl have been exploited to identify second-generation drugs that override acquired target resistance. These insights have created a rationale for the development of either multi-targeted protein kinase inhibitors or cocktails of selective antagonists as antitumour drugs that combine increased therapeutic potency with a reduced risk of the emergence of molecular resistance.
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PMID:Strategies to overcome resistance to targeted protein kinase inhibitors. 1557 99

Following G protein-coupled receptors (GPCRs), protein kinases have become the second most important class of targets for drug discovery over the last 20 years. While only four kinase inhibitors have reached the market to date (Fasudil for rho-dependent kinase, Rapamycin for TOR, Gleevec for BCR-Abl, and Iressa for EGFR), many more are already in clinical development. A historical overview of kinase inhibitors was recently published by Cohen. [1] After the previous successes, protein kinases are now regarded as attractive, well-drugable targets, and the analysis of the human genome has yielded 518 protein kinases. [2] We can thus expect screening for protein kinase inhibitors to become even more important in the future. In this review we will focus on the early steps of drug discovery programs producing new lead compounds. We will guide the reader through efficient state-of-the-art assay development and high-throughput screening of large chemical libraries for protein kinase inhibitors.
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PMID:High-throughput screening for kinase inhibitors. 1574 84

Imatinib mesylate is a novel anti-tumor agent useful in the clinical management of chronic myelogenous leukemia and gastrointestinal stromal tumors with minimal toxicity relative to other forms of cancer therapy. Its clinical activity and minimal toxicity are related to specific inhibition of cellular targets including BCR-ABL, platelet-derived growth factor receptor and c-kit kinases, resulting in the collapse of downstream signaling cascades important for transformation. In some patients, unexpected toxicities arise that are not associated with inhibition of any known cellular imatinib target. In this report, we investigated the effects of imatinib on squamous carcinoma cell signaling. Imatinib induced expression of COX-2 in a dose-dependent manner with concomitant accumulation of prostaglandin E2. COX-2 induction by imatinib was initiated through epidermal growth factor (EGF) receptor kinase activation and downstream signaling through mitogenic-activated protein kinase. COX-2 induction by imatinib was blocked by MEK1 or EGF receptor inhibition. Imatinib did not activate stressor cytokine-signaling pathways (p38 kinase, nuclear factor-kB nuclear translocation) or affect COX-1 expression. Imatinib failed to activate EGF receptor signals in other tumor types, suggesting that COX-2 induction in imatinib-treated cells is mediated through release of autocrine factors expressed or activated in squamous tumors. COX-2 induction by imatinib in squamous tumors derived from the head and neck region is unique with respect to other target-specific agents and may represent one of the unintended toxic effects of imatinib described in some patients.
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PMID:Cyclooxygenase-2 induction and prostaglandin E2 accumulation in squamous cell carcinoma as a consequence of epidermal growth factor receptor activation by imatinib mesylate. 1584 61

Imatinib mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients.
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PMID:Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. 1588 38

The breakpoint cluster region protein, BCR, has protein kinase activity that can auto- and trans-phosphorylate serine, threonine and tyrosine residues. BCR has been implicated in chronic myelogenous leukaemia as well as important signalling pathways, and as such its interaction with 14-3-3 is of major interest. 14-3-3tau and zeta isoforms have been shown previously to be phosphorylated in vitro and in vivo by BCR kinase on serine and threonine residue(s) but site(s) were not determined. Phosphorylation of 14-3-3 isoforms at distinct sites is an important mode of regulation that negatively affects interaction with Raf kinase and Bax, and potentially influences the dimerization of 14-3-3. In this study we have further characterized the BCR-14-3-3 interaction and have identified the site phosphorylated by BCR. We show here that BCR interacts with at least five isoforms of 14-3-3 in vivo and phosphorylates 14-3-3tau on Ser233 and to a lesser extent 14-3-3zeta on Thr233. We have previously shown that these two isoforms are also phosphorylated at this site by casein kinase 1, which, in contrast to BCR, preferentially phosphorylates 14-3-3zeta.
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PMID:BCR kinase phosphorylates 14-3-3 Tau on residue 233. 1604 49

To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved "gatekeeper" threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib- and BMS-354825-resistant ABL(T315I) kinase. The KIT/FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D/T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitinib- and erlotinib-resistant EGFR(L858R/T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib/erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.
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PMID:Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. 1604 38

Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway. mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1. As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest. Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR. New rapamycin analogs including CCI-779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.
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PMID:Mammalian target of rapamycin as a therapeutic target in leukemia. 1630 91

The pre-B-cell receptor (pre-BCR) is thought to signal transcriptional activation of the immunoglobulin light (L) chain gene locus, proceeding to its V-J rearrangement. The pre-BCR signaling pathway for this process is largely unknown but may involve the adaptor protein BASH (BLNK/SLP-65). Here we report that the pre-B leukemia cell lines established from affected BASH-deficient mice rearrange kappaL-chain gene locus and down-regulate pre-BCR upon PMA treatment or BASH reconstitution. Analyses with specific inhibitors revealed that activation of novel PKC (nPKC) and MEK, but not Ras, is necessary for the rearrangement. Accordingly, retroviral transduction of active PKCeta, PKCepsilon, or Raf-1, but not Ras, induced the kappa gene rearrangement and expression in the pre-B-cell line. Tamoxifen-mediated BASH reconstitution resulted in the translocation of PKCeta to the plasma membrane and kappa chain expression. These data make evident that the Ras-independent BASH-nPKC-Raf-1 pathway of pre-BCR signaling induces the L-chain gene rearrangement and expression.
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PMID:BASH-novel PKC-Raf-1 pathway of pre-BCR signaling induces kappa gene rearrangement. 1679 53

The Ras/Raf/MEK/ERK and PI3K/PTEN/AKT signaling cascades play critical roles in the transmission of signals from growth factor receptors to regulate gene expression and prevent apoptosis. Components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf, PI3K, PTEN, Akt). Also, mutations occur at genes encoding upstream receptors (e.g., EGFR and Flt-3) and chimeric chromosomal translocations (e.g., BCR-ABL) which transmit their signals through these cascades. These pathways interact with each other to regulate growth and in some cases tumorigenesis. For example, in some cells, PTEN mutation may contribute to suppression of the Raf/MEK/ERK cascade due to the ability of elevated activated Akt levels to phosphorylate and inactivate Raf-1. We have investigated the genetic structures and functional roles of these two signaling pathways in the malignant transformation and drug resistance of hematopoietic, breast and prostate cancer cells. Although both of these pathways are commonly thought to have anti-apoptotic and drug resistance effects on cells, they display different cell-lineage-specific effects. Induced Raf expression can abrogate the cytokine dependence of certain hematopoietic cell lines (FDC-P1 and TF-1), a trait associated with tumorigenesis. In contrast, expression of activated PI3K or Akt does not abrogate the cytokine dependence of these hematopoietic cell lines, but does have positive effects on cell survival. However, activated PI3K and Akt can synergize with activated Raf to abrogate the cytokine dependence of another hematopoietic cell line (FL5.12) which is not transformed by activated Raf expression by itself. Activated Raf and Akt also confer a drug-resistant phenotype to these cells. Raf is more associated with proliferation and the prevention of apoptosis while Akt is more associated with the long-term clonogenicity. In breast cancer cells, activated Raf conferred resistance to the chemotherapeutic drugs doxorubicin and paclitaxel. Raf induced the expression of the drug pump Mdr-1 (a.k.a., Pgp) and the Bcl-2 anti-apoptotic protein. Raf did not appear to induce drug resistance by altering p53/p21Cip-1 expression, whose expression is often linked to regulation of cell cycle progression and drug resistance. Deregulation of the PI3K/PTEN/Akt pathway was associated with resistance to doxorubicin and 4-hydroxyl tamoxifen, a chemotherapeutic drug and estrogen receptor antagonist used in breast cancer therapy. In contrast to the drug-resistant breast cancer cells obtained after overexpression of activated Raf, cells expressing activated Akt displayed altered (decreased) levels of p53/p21Cip-1. Deregulated expression of the central phosphatase in the PI3K/PTEN/Akt pathway led to breast cancer drug resistance. Introduction of mutated forms of PTEN, which lacked lipid phosphatase activity, increased the resistance of the MCF-7 cells to doxorubicin, suggesting that these lipid phosphatase deficient PTEN mutants acted as dominant negative mutants to suppress wild-type PTEN activity. Finally, the PI3K/PTEN/Akt pathway appears to be more prominently involved in prostate cancer drug resistance than the Raf/MEK/ERK pathway. Some advanced prostate cancer cells express elevated levels of activated Akt which may suppress Raf activation. Introduction of activated forms of Akt increased the drug resistance of advanced prostate cancer cells. In contrast, introduction of activated forms of Raf did not increase the drug resistance of the prostate cancer cells. In contrast to the results observed in hematopoietic cells, Raf may normally promote differentiation in prostate cells which is suppressed in advanced prostate cancer due to increased expression of activated Akt arising from PTEN mutation. Thus in advanced prostate cancer it may be advantageous to induce Raf expression to promote differentiation, while in hematopoietic cancers it may be beneficial to inhibit Raf/MEK/ERK-induced proliferation. These signaling and anti-apoptotic pathways can have different effects on growth, prevention of apoptosis and induction of drug resistance in cells of various lineages which may be due to the expression of lineage-specific factors.
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PMID:Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. 1685 53


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