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)

Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis. There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Attempts to optimize a cyclin-dependent kinase-1 (CDK1) inhibitor by using palladium-catalyzed C-C bond, C-N bond formation reactions to assemble diverse biheteroaryl molecules led to the unexpected discovery of a pyrazine-pyridine biheteroaryl as a novel series of potent VEGFR-2 inhibitors. Compound 15, which had IC(50) = 0.084 microM at VEGFR-2, showed very modest selectivity against fibroblast growth factor receptor-2 (IC(50) = 0.21 microM), platelet-derived growth factor receptor (IC(50) = 0.36 microM), and glycogen synthase kinase-3 (IC(50) = 0.478 microM), while it exhibited more than 10-fold selectivity against epidermal growth factor receptor (IC(50) = 1.36 microM) and insulin-R kinase (IC(50) = 1.69 microM). On the other hand, compound 15 exhibited more than 100-fold selectivity against calmodulin kinase 2; casein kinase-1 and -2; CDK1 and -4; mitogen-activated protein kinase; and protein kinase A, Cbeta2, and Cgamma (IC(50) >10 microM). Compound 15 also displayed high inhibitory potency on VEGF-stimulated human umbilical vein endothelial cell (HUVEC) proliferation (IC(50) = 0.005 microM) and good selectivity against cell lines such as HUVEC, human aortic smooth muscle cells, and MRC5 lung fibroblasts. Molecular docking studies were conducted in an attempt to rationalize the unexpected high VEGFR-2 selectivity of 15.
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PMID:Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors. 1577 33

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800 mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400 mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity.
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PMID:Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. 1587 Jul 16

There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Palladium-catalyzed C-C bond, C-N bond formation reactions were used to assemble various pyrazine-pyridine biheteroaryls as potent VEGFR-2 inhibitors. Among them, 4-{5-[6-(3-chloro-phenylamino)-pyrazin-2-yl]-pyridin-3-ylamino}-butan-1-ol (39) and N-{5-[6-(3-chloro-phenylamino)-pyrazin-2-yl]-pyridin-3-yl}-N',N'-dimethyl-ethane-1,2-diamine (41) exhibited the highest kinase selectivity against fibroblast growth factor receptor kinase, platelet-derived growth factor receptor kinase, and glycogen synthase kinase-3. All of these compounds showed good cellular potency to inhibit VEGF-stimulated proliferation of human umbilical vein endothelial cells (HUVEC) but with modest effects on the unstimulated growth of HUVEC. The low inhibition of these compounds to the growth of tumor cell lines, such as HeLa, HCT-116, and A375 further confirms that these VEGFR-2 inhibitors are not cytotoxic agents. The in vivo antitumor activity of 39 and 41 were demonstrated in the A375 human melanoma xenograft nude mice model. Molecular modeling (QSAR analysis) was conducted in an attempt to rationalize the observed structure-activity relationship.
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PMID:Synthesis and structure-activity relationships of pyrazine-pyridine biheteroaryls as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors. 1603 69

We have previously shown that hypoxia makes vascular smooth muscle cells (VSMCs) responsive to placental growth factor (PlGF) through the induction of functional fms-like tyrosine kinase (Flt-1) receptors. The aim of this study was to investigate the molecular mechanisms involved in the PlGF effects on proliferation and contraction of VSMCs previously exposed to hypoxia (3% O2). In cultured rat VSMCs exposed to hypoxia, PlGF increased the phosphorylation of protein kinase B (Akt), p38 and STAT3; activation of STAT3 was higher than that of other kinases. In agreement with this finding, the proliferation of hypoxia-treated VSMCs in response to PlGF was significantly impaired by the p38 and the phosphatidylinositol 3-kinase inhibitors SB202190 and LY294002, respectively, and was almost completely prevented by AG490, a janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor. Since hypoxia was able to reverse the vasorelaxant effect of PlGF into a vasoconstrictor response, the mechanism of this latter effect was also investigated. Significant Flt-1 activity was measured in isolated preparations from rat aorta exposed to hypoxia. Inhibitors of mitogen-activated protein kinase kinase, Akt and STAT3 induced a modest inhibition of the vasoconstrictor response to PlGF, while the p38 inhibitor SB202190 markedly impaired the PlGF-induced contractile response. These effects were selectively mediated by Flt-1 without any involvement of foetal liver kinase-1 receptors. These data are the first evidence that different intracellular pathways activated by Flt-1 receptor in VSMCs are involved in diverse biological effects of PlGF: while mitogen activated protein kinase kinase/extracellular signal regulated kinase(1/2) and JAK/STAT play a role in VSMC proliferation, p38 is involved in VSMC contraction. These findings may highlight the role of PlGF in vascular pathology.
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PMID:Intracellular pathways triggered by the selective FLT-1-agonist placental growth factor in vascular smooth muscle cells exposed to hypoxia. 1608 34

Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, significant advances in understanding the molecular mechanisms underlying RCC have led to the development of rationally designed therapies, which are now being tested clinically. To date, the vascular endothelial growth factor receptor (VEGFR) pathway has been the most promising target, and two agents (BAY 43-9006 and SU 11248) that inhibit not only VEGFR but also other receptors, including platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT3), KIT, and Raf kinase, were recently approved by the FDA for advanced RCC. In addition, a phase III trial investigating the addition of VEGF inhibition to interferon alpha (IFN-alpha) in RCC is also now going on. Although the clinical activity of existing agents is to be further defined in ongoing trials, the exciting clinical response data with VEGF inhibition in RCC have demonstrated a key role in the treatment of this historically resistant malignancy.
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PMID:Molecular targeting therapy for renal cell carcinoma. 1685 Jan 27

A global gene expression profiling of TSH stimulation on differentiated (FRTL5) and partially dedifferentiated [FRT/TSHR (TSH receptor)] rat thyroid cells was performed. A total of 123 TSH-regulated genes (95 newly described) were identified in FRTL5, whereas no significant transcriptional modifications were seen in FRT/TSHR cells. Because regulatory subunit IIbeta (RIIbeta) of protein kinase A (PKA), a key element downstream of cAMP, was expressed in FRTL5 but not in cAMP-refractory FRT/TSHR cells, we hypothesized that this gene may play an important role in TSH signaling. We therefore performed a series of experiments to investigate the involvement of RIIbeta and the different PKA isoforms. A positive effect of PKA II- but not of PKA I-selective activation on gene transcription and proliferation in FRTL5 cells, as well as an impairment of TSH nuclear effects after RIIbeta silencing were observed, suggesting that PKA II plays an essential role in TSH signaling. This view was supported by the restoration of TSH nuclear effects after reexpression of RIIbeta in FRT/TSHR cells. Because PKA I stimulation could increase iodide uptake in FRTL5 cells without affecting gene transcription, PKA I may mediate TSH actions at posttranscriptional levels. Analyses on three human cancer cell lines confirmed the possible loss of RIIbeta expression and antiproliferative activity of PKA I-selective cAMP analogs ( approximately 60% at 200 microm in BRAF-mutated cells). The inhibitory effect of PKA I apparently required constitutive MAPK activation and was associated with an inhibition of ERK phosphorylation. These findings may open new therapeutic perspectives in patients with thyroid cancer.
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PMID:Selective modulation of protein kinase A I and II reveals distinct roles in thyroid cell gene expression and growth. 1688 86

Improvements in our understanding of the molecular basis of cancer have led to the clinical development of protein kinase inhibitors, which target pivotal molecules involved in intracellular signaling pathways implicated in tumorigenesis and progression. These novel targeted agents have demonstrated activity against a wide range of solid tumors, are generally better tolerated than standard chemotherapeutics, and may revolutionize the management of advanced refractory cancer. The ubiquitous Raf serine/threonine kinases are pivotal molecules within the Raf/mitogen extracellular kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway, which regulates cellular proliferation and survival. Raf kinase isoforms (wild-type Raf-1 or the b-raf V600E oncogene) are overactivated in a variety of solid tumor types, including renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), melanoma, and papillary thyroid carcinoma. In this review, the role of Raf in normal cells and in cancer is discussed, and an overview is given of Raf inhibitors currently in development, focusing on sorafenib tosylate (BAY 43-9006 or sorafenib). Sorafenib is the first oral multi-kinase inhibitor to be developed that targets Raf kinases (Raf-1, wild-type B-Raf, and b-raf V600E), in addition to receptor tyrosine kinases associated with angiogenesis (vascular endothelial growth factor receptor [VEGFR]-2/-3, platelet-derived growth factor receptor [PDGFR]-beta) or tumor progression (Flt-3, c-kit). Preclinical and clinical sorafenib data that led to its recent approval for the treatment of advanced RCC are summarized, along with current thinking on sorafenib's mechanism of effect on the tumor and tumor vasculature in melanoma and RCC.
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PMID:Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. 1689 Jul 95

Mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) are activated in the majority of gliomas and contribute to tumor cell growth and survival. Sorafenib (Bay43-9006; Nexavar) is a dual-action Raf and vascular endothelial growth factor receptor inhibitor that blocks receptor phosphorylation and MAPK-mediated signaling and inhibits growth in a number of tumor types. Because our initial studies of this agent in a series of glioma cell lines showed only partial growth inhibition at clinically achievable concentrations, we questioned whether inhibition of PKC signaling using the PKC-delta inhibitor rottlerin might potentiate therapeutic efficacy. Proliferation assays, apoptosis induction studies, and Western immunoblot analysis were conducted in cells treated with sorafenib and rottlerin as single agents or in combination. Sorafenib and rottlerin reduced proliferation in all cell lines when used as single agents, and the combination produced marked potentiation of growth inhibition. Flow-cytometric measurements of cells stained with Annexin V-propidium iodide and immunocytochemical assessment of cytochrome c and apoptosis-inducing factor release demonstrated that addition of rottlerin resulted in significantly higher levels of apoptosis than sorafenib alone. In addition, the combination of sorafenib and rottlerin reduced or completely inhibited the phosphorylation of extracellular signal-regulated kinase and Akt and down-regulated cell cycle regulatory proteins such as cyclin-D1, cyclin-D3, cyclin-dependent kinase (cdk)4, and cdk6 in a dose- and time-dependent manner. Our results clearly indicate that inhibition of PKC-delta signaling enhances the antiproliferative effect of sorafenib in malignant human glioma cell lines and support the examination of combinations of signaling inhibitors in these tumors.
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PMID:Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. 1695 60

We previously reported that vascular endothelial growth factor (VEGF) increases vascular permeability through the synthesis of endothelial platelet-activating factor (PAF), while others reported the contribution of nitric oxide (NO). Herein, we addressed the contribution of VEGF receptors and the role played by PAF and NO in VEGF-induced plasma protein extravasation. Using a modified Miles assay, intradermal injection in mice ears of VEGF-A(165), VEGF-A(121), and VEGF-C (1 microM) which activate VEGFR-2 (Flk-1) receptor increased vascular permeability, whereas a treatment with VEGFR-1 (Flt-1) analogs; PlGF and VEGF-B (1 microM) had no such effect. Pretreatment of mice with PAF receptor antagonist (LAU8080) or endothelial nitric oxide synthase (eNOS) inhibitor (L-NAME) abrogated protein extravasation mediated by VEGF-A(165). As opposed to PAF (0.01-1 microM), treatment with acetylcholine (ACh; up to 100 microM; inducer of NO synthesis) or sodium nitroprusside (SNP; up to 1 microM; NO donor) did not induce protein leakage. Simultaneous pretreatment of mice with eNOS and protein kinase A (PKA) inhibitors restored VEGF-A(165) vascular hyperpermeability suggesting that endogenous NO synthesis leads to PKA inhibition, which support maintenance of vascular integrity. Our data demonstrate that VEGF analogs increase vascular permeability through VEGFR-2 activation, and that both endogenous PAF and NO synthesis contribute to VEGF-A(165)-mediated vascular permeability. However, PAF but not NO directly increases vascular permeability per se, thereby, suggesting that PAF is a direct inflammatory mediator, whereas NO serves as a cofactor in VEGF-A(165) proinflammatory activities.
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PMID:Vascular permeability induced by VEGF family members in vivo: role of endogenous PAF and NO synthesis. 1711 9

Vascular endothelial growth factor (VEGF), a potent mediator of endothelial proliferation and migration, has an important role also in brain edema formation during hypoxia and ischemia. VEGF binds to the tyrosine kinase receptors Flt-1 and Flk-1. Yet, their relative importance for hypoxia-induced hyperpermeability is not well understood. We used an in vitro blood-brain barrier (BBB) model consisting of porcine brain microvascular endothelial cells (BMEC) to determine the role of Flt-1 in VEGF-induced endothelial cell (EC) barrier dysfunction. Soluble Flt-1 abolished hypoxia/VEGF-induced hyperpermeability. Furthermore, selective antisense oligonucleotides to Flt-1, but not to Flk-1, inhibited hypoxia-induced permeability changes. Consistent with these data, addition of the receptor-specific homolog placenta-derived growth factor, which binds Flt-1 but not Flk-1, increased endothelial permeability to the same extent as VEGF, whereas adding VEGF-E, a viral VEGF molecule from the orf virus family activating Flk-1 and neuropilin-1, but not Flt-1, did not show any effect. Using the carcinoma submandibular gland cell line (CSG), only expressing Flt-1, it was demonstrated that activation of Flt-1 is sufficient to induce hyperpermeability by hypoxia and VEGF. Hyperpermeability, induced by hypoxia/VEGF, depends on activation of phosphatidylinositol 3-kinase/Akt (PI3-K/Akt), nitric oxide synthase (NOS) and protein kinase G (PKG). The activation of the PI3-K/Akt pathway by hypoxia was confirmed using an in vivo mice hypoxia model. These results demonstrate that hypoxia/VEGF-induced hyperpermeability can be mediated by activation of Flt-1 independently on the presence of Flk-1 and indicate a central role for activation of the PI3-K/Akt pathway, followed by induction of NOS and PKG activity.
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PMID:Flt-1, but not Flk-1 mediates hyperpermeability through activation of the PI3-K/Akt pathway. 1731


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