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 protein kinase inhibitors show great promise as anti-cancer agents, however, de novo and acquired resistance present problems. These are reviewed and illustrated using the receptor tyrosine kinase, KIT, as an example. Emerging solutions are presented, such as targeting active kinase conformations.
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PMID:Small molecule inhibitors of protein kinases in cancer- how to overcome resistance. 1707 10

Gastrointestinal (GI) stromal tumors (GISTs) are the most common mesenchymal tumors specific to the GI tract, generally defined as KIT (CD117)-positive tumors with a characteristic set of histologic features. These tumors, derived from Cajal cells or their precursors, most commonly occur at the age >50 years in the stomach (60%), jejunum and ileum (30%), duodenum (4-5%), rectum (4%), colon and appendix (1-2%), and esophagus (<1%), and rarely as apparent primary extragastrointestinal tumors in the vicinity of stomach or intestines. Their overall incidence has been estimated as 10 to 20 per million, including incidental minimal tumors. GISTs are rare in children (<1%) and almost exclusively occur in stomach. They are common in patients with neurofibromatosis 1, who have a predisposition to (multiple) small intestinal GISTs. GISTs contain a spectrum from minute indolent tumors to sarcomas at all sites of occurrence. Their gross patterns are diverse, including nodular, cystic, and diverticular tumors. External involvement of pancreas and liver can simulate primary tumor in these organs. In general, gastric tumors have a more favorable prognosis than the intestinal ones with similar parameters. Gastric GISTs < or =10 cm and < or =5 mitoses per 50 HPFs have a low risk for metastasis, whereas those with >5 per 50 HPFs and >5 cm in diameter have a high risk for metastasis. In contrast, all intestinal GISTs >5 cm independent of mitotic rate have at least moderate risk for metastases, and all >5 mitoses per 50 HPFs have a high risk for metastases. Intestinal GISTs < or =5 cm with < or =5 mitoses per 50 HPFs have a low risk for metastases. Gastric GISTs can be divided into histologic subgroups including 4 spindle cell and 4 epithelioid variants. Intestinal GISTs are a histologically more homogeneous group and often contain distinctive extracellular collagen globules, skeinoid fibers. Immunohistochemical demonstration of KIT, CD34, or protein kinase theta positivity helps to properly identify these tumors.
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PMID:Gastrointestinal stromal tumors: pathology and prognosis at different sites. 1719 20

We investigated the antiproliferative effect of genistein, and its antileukemia effect in combination with cytosine arabinoside (ara-C) in acute myeloid leukemia (AML). Optimal dosage of genistein as single agent and in combination with ara-C was first determined in vitro. Genistein demonstrated a dose- and time-dependent inhibition of cell proliferation, induction of apoptosis, and cell-cycle arrest at G(2)/M phase. Gene-expression profiles revealed mitogen-activated protein kinase (MAPK) signaling as one of the most affected biological pathways. Phosphatidylinositol 3 kinase, protein kinase A, protein kinase C, MAPK kinase 4, KIT, PIM1, and transforming growth factor-beta receptor 1, were significantly downregulated by genistein. To test whether genistein could augment the antiproliferation activity of ara-C, two groups of severe combined immunodeficient mice were inoculated with NB4 and HL-60 cells, respectively, followed by treatment with either genistein or combination of genistein and ara-C. The combination treatment significantly inhibited tumor growth, and improved survival of NB4 (p = 0.0031) and HL-60 (p = 0.0007) xenograft mice. Our present study highlighted the schedule-dependent synergistic antileukemia effect of genistein with chemotherapy in both in vitro and in vivo models. This novel combination could potentially be a promising regimen for treatment of AML.
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PMID:Synergistic antileukemia effect of genistein and chemotherapy in mouse xenograft model and potential mechanism through MAPK signaling. 1719 76

Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GISTs), and the KIT/PDGFRA kinase inhibitor, imatinib, is standard of care for patients with metastatic GIST. However, most of these patients eventually develop clinical resistance to imatinib and other KIT/PDGFRA kinase inhibitors and there is an urgent need to identify novel therapeutic strategies. We reported previously that protein kinase C-theta (PKCtheta) is activated in GIST, irrespective of KIT or PDGFRA mutational status, and is expressed at levels unprecedented in other mesenchymal tumors, therefore serving as a diagnostic marker of GIST. Herein, we characterize biological functions of PKCtheta in imatinib-sensitive and imatinib-resistant GISTs, showing that lentivirus-mediated PKCtheta knockdown is accompanied by inhibition of KIT expression in three KIT+/PKCtheta+ GIST cell lines, but not in a comparator KIT+/PKCtheta- Ewing's sarcoma cell line. PKCtheta knockdown in the KIT+ GISTs was associated with inhibition of the phosphatidylinositol-3-kinase/AKT signaling pathway, upregulation of the cyclin-dependent kinase inhibitors p21 and p27, antiproliferative effects due to G(1) arrest and induction of apoptosis, comparable to the effects seen after direct knockdown of KIT expression by KIT short-hairpin RNA. These novel findings highlight that PKCtheta warrants clinical evaluation as a potential therapeutic target in GISTs, including those cases containing mutations that confer resistance to KIT/PDGFRA kinase inhibitors.
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PMID:Protein kinase C-theta regulates KIT expression and proliferation in gastrointestinal stromal tumors. 1852 Oct 81

Imatinib, nilotinib and dasatinib are protein kinase inhibitors which target the tyrosine kinase activity of the Breakpoint Cluster Region-Abelson kinase (BCR-ABL) and are used to treat chronic myelogenous leukemia. Recently, using a chemical proteomics approach another tyrosine kinase, the collagen receptor Discoidin Domain Receptor1 (DDR1) has also been identified as a potential target of these compounds. To further investigate the interaction of imatinib, nilotinib and dasatinib with DDR1 kinase we cloned and expressed human DDR1 and developed biochemical and cellular functional assays to assess their activity against DDR1 and the related receptor tyrosine kinase Discoidin Domain Receptor2 (DDR2). Our studies demonstrate that all 3 compounds are potent inhibitors of the kinase activity of both DDR1 and DDR2. In order to investigate the question of selectivity among DDR1, DDR2 and other tyrosine kinases we have aligned DDR1 and DDR2 protein sequences to other closely related members of the receptor tyrosine kinase family such as Muscle Specific Kinase (MUSK), insulin receptor (INSR), Abelson kinase (c-ABL), and the stem cell factor receptor (c-KIT) and have built homology models for the DDR1 and DDR2 kinase domains. In spite of high similarity among these kinases we show that there are differences within the ATP-phosphate binding loop (P-loop), which could be exploited to obtain kinase selective compounds. Furthermore, the potent DDR1 and DDR2 inhibitory activity of imatinib, nilotinib and dasatinib may have therapeutic implications in a number of inflammatory, fibrotic and neoplastic diseases.
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PMID:Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. 1893 56

In addition to regulating mast cell homeostasis, the activation of KIT following ligation by stem cell factor promotes a diversity of mast cell responses, including cytokine production and chemotaxis. Although we have previously defined a role for the mammalian target of rapamycin complex 1 in these responses, it is clear that other signals are also required for maximal KIT-dependent cytokine production and chemotaxis. In this study, we provide evidence to support a role for glycogen synthase kinase 3beta (GSK3beta) in such regulation in human mast cells (HuMCs). GSK3beta was observed to be constitutively activated in HuMCs. This activity was inhibited by knockdown of GSK3beta protein following transduction of these cells with GSK3beta-targeted shRNA. This resulted in a marked attenuation in the ability of KIT to promote chemotaxis and, in synergy with FcepsilonRI-mediated signaling, cytokine production. GSK3beta regulated KIT-dependent mast cell responses independently of mammalian target of rapamycin. However, evidence from the knockdown studies suggested that GSK3beta was required for activation of the MAPKs, p38, and JNK and downstream phosphorylation of the transcription factors, Jun and activating transcription factor 2, in addition to activation of the transcription factor NF-kappaB. These studies provide evidence for a novel prerequisite priming mechanism for KIT-dependent responses regulated by GSK3beta in HuMCs.
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PMID:Glycogen synthase kinase 3beta activation is a prerequisite signal for cytokine production and chemotaxis in human mast cells. 2000 84

Metastatic melanoma remains an aggressive malignancy conferring a very poor prognosis, and standard chemotherapeutic and immunologic treatments have not demonstrated an overall survival benefit. No molecularly targeted therapy is approved for the treatment of advanced melanoma. Melanoma is a molecularly heterogeneous malignancy, and optimal treatment in a given patient is likely to depend on the presence of specific molecular abnormalities. Aberrations in components of signal transduction pathways have been identified that modulate melanoma proliferation and survival. Mutations that activate the mitogen activated protein kinase (MAPK) pathway via BRAF or NRAS are present in the majority of melanomas arising on skin intermittently exposed to the sun. Mutations that activate the KIT oncogene are more commonly present in melanomas arising from mucosal, acral, or chronic sun-damaged sites. Inhibitors of the MAPK pathway and of KIT are currently undergoing clinical investigation. In this article, we review advances in targeted strategies to treat different subgroups of patients with melanoma.
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PMID:Advances in targeted therapy for melanoma. 2115 11

Melanoma is an aggressive disease with few standard treatment options. The conventional classification system for this disease is based on histological growth patterns, with division into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. Major limitations of this classification system are absence of prognostic importance and little correlation with treatment outcomes. Recent preclinical and clinical findings support the notion that melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma has great implications for development of new and effective treatments. Genes of the mitogen-associated protein kinase (MAPK) pathway harbour alterations sometimes identified in people with melanoma. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with sensitivity in vitro and in vivo to agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. Some uveal melanomas have activating mutations in GNAQ and GNA11, rendering them potentially susceptible to MEK inhibition. These findings suggest that prospective genotyping of patients with melanoma should be used increasingly as we work to develop new and effective treatments for this disease.
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PMID:Treatment implications of the emerging molecular classification system for melanoma. 2134 66

Protein kinases play several pertinent roles in cell proliferation, and targeting these proteins has been shown to be a successful strategy toward controlling different malignancies. Despite the great discovery stories during the last two decades, there is still a demand for anticancer small molecules with the potential of being selective on both the protein kinase and/or the cellular level. A series of novel piperazinylpyrimidine compounds were synthesized and tested for their potential to selectively inhibit the growth of certain tumor cell lines included within the NCI-60 cell line panel. MDA-MB-468, a triple-negative/basal-like breast carcinoma, cell line was among the most sensitive cell lines towards compounds 4 and 15. The three most interesting compounds identified in cellular screens (4, 15, and 16) were subjected to kinase profiling and found to have an interesting selective tendency to target certain kinase subfamily members; PDGFR, CK1, RAF and others. Compound 4 showed a selective tendency to bind to and/or inhibit the function of certain KIT and PDGFRA mutants compared to their wild-type isoforms. Piperazinylpyrimidine based derivatives represent a new class of selective kinase inhibitors. Significantly 4 is more potent at inhibiting oncogenic mutant forms of PDGFR family kinases, which is relevant in terms of its potential use in treating tumors that have become resistant to treatment or driven by such mutations. The clinical demand for agents useful in the control of triple-negative/basal-like breast cancer justifies our interest in compound 15 which is a potent growth inhibitor of MDA-MB-468 cell line.
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PMID:Discovery, synthesis, and investigation of the antitumor activity of novel piperazinylpyrimidine derivatives. 2142 32

Cutaneous melanoma is a highly aggressive cancer with still limited, but increasingly efficacious, standard treatment options. Recent preclinical and clinical findings support the notion that cutaneous melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma already has great implications for the management of cutaneous melanoma. Herein, we review our rapidly growing understanding of the molecular biology of cutaneous melanoma, including the pathogenic roles of the mitogen-associated protein kinase (MAPK) pathway, the phosphatidylinositol 3 kinase [PI3K]/phosphatase and tensin homologue deleted on chromosome 10 [PTEN]/Akt/mammalian target of rapamycin [mTOR])PTEN (phosphatase and tensin homolog) pathway, MET (hepatocyte growth factor), Notch signaling, and other key molecules regulating cell cycle progression and apoptosis. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with clinical benefit from agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Cutaneous melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. These findings suggest that prospective genotyping of patients with melanoma, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, should be used increasingly as we work to develop new and more effective treatments for this devastating disease.
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PMID:The molecular pathology of cutaneous melanoma. 2211 80


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