Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines have been identified as a novel class of potent EGF-R protein tyrosine kinase inhibitors. In an interactive process, this class of compounds was then optimized. 13, 14, 28, 36, 37, and 44, the most potent compounds of this series, inhibited the EGF-R PTK with IC50 values in the low nanomolar range. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, v-Abl) and serine/threonine kinases (PKC alpha, PKA) was observed. Kinetic analysis revealed competitive type kinetics relative to ATP. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 36, 37, and 44 at IC50 values between 0.1 and 0.4 microM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 microM. In addition, these compounds were able to selectively inhibit c-fos mRNA expression in EGF-dependent cell lines with IC50 values between 0.1 and 2 microM, but did not affect c-fos mRNA induction in response to PDGF or PMA (IC50 >100 microM). Proliferation of the EGF-dependent MK cell line was inhibited with similar IC50 values. From SAR studies, a binding mode for 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines as well as for the structurally related 4-(phenylamino)quinazolines at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)7H-pyrrolo[2,3-d]pyrimidines therefore represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.
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PMID:4-(Phenylamino)pyrrolopyrimidines: potent and selective, ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase. 869 23

Members of three classes of pyridinylimidazoles bind with varying affinities to CSBP (p38) kinase which is a member of a stress-induced signal transduction pathway. Based upon SAR and protein homology modeling, the pharmacophore and three potential modes of binding to the enzyme are presented. For a subset of pyridinylimidazoles, binding is shown to correlate with inhibition of CSBP kinase activity, whereas no significant inhibition of PKA, PKC alpha and ERK kinase activity is observed.
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PMID:Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. 904 57

We have explored the effects of PCBs on Ca(2+)-homeostasis and inositol phosphates in an attempt to understand cellular mechanism(s) for neurotoxicity of PCBs. The selected prototypic congeners have non-dioxin-like (2,2'-dichlorobiphenyl; 2,2'-DCB; IUPAC # 4; ortho-substituted) and dioxin-like (3,3',4,4',5-pentachlorobiphenyl; 3,3',4,4',5-PeCB; IUPAC # 126; non-ortho substituted) properties. The hypothesis is that some PCBs in vitro alter Ca(2+)-homeostasis and interfere with intracellular second messengers. One of the consequences of this perturbation is protein kinase C (PKC) translocation, and these events could lead to cytotoxicity. Our results indicate that the non-dioxin like PCB (ortho-substituted one) is active in vitro and perturbed signal transduction mechanism including Ca(2+)-homeostasis and PKC translocation. The effects were seen at relatively low concentrations (5-50 microM), whereas higher concentrations (> 200 microM) were required to produce cytotoxicity. Results from SAR, in general, indicate that congeners with chlorine substitutions at ortho-position or low lateral substitutions (mostly meta-) are active in vitro where as non-ortho congeners are inactive. In summary, these results indicate that low lateral substitution (especially without para-substitution that favor coplanarity) or high lateral content in the presence of ortho-substitution (to hinder coplanarity) may be the most critical structural requirement underlying the activity of PCB congeners in vitro. Additional experiments with polychlorinated diphenyl ethers (PCDEs) and their analogs, where coplanarity is difficult regardless of degree and pattern of chlorination, provided important information supporting our hypothesis that coplanarity plays a key role in the activity of PCBs in vitro. For example, a PCB congener with 3,3',4,4'-chlorine substitutions is not active whereas a PCDE with the same chlorine substitutions is active. Similarity, 4,4'-DCB is not active whereas PCDE with 4,4'-substitutions is active. One major structural difference in PCDE when compared to the corresponding PCB is non-coplanarity. The PCBs compared here are coplanar and not active, whereas PCDEs are non-coplanar and active in vitro in neuronal preparations. Molecular mechanics calculations and conformational searches confirmed the extent of coplanarity among PCBs and PCDEs. Non-ortho PCBs are more coplanar in nature when compared to ortho-PCBs and PCDEs. These results demonstrate that the extent of coplanarity of certain chlorinated aromatic hydrocarbons can affect their potency in vitro, and ortho-substitutions on the biphenyl, which increase non-coplanarity, are characteristics of the most active PCB congeners.
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PMID:Structure-activity relationships of potentially neurotoxic PCB congeners in the rat. 929 92

In the course of the random screening of a pool of CIBA chemicals, the two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors of the EGF-R tyrosine kinase. Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), the class of the pyrazolo[3,4-d]pyrimidines was then optimized in an interactive process leading to a series of 4-(phenylamino)-1H-pyrazolo[3,4-d]-pyrimidines as highly potent inhibitors of the EGF-R tyrosine kinase. The most potent compounds 13, 14, 15, 17, 19, 22, 26, 28, and 30 of this series inhibited the EGF-R PTK with IC50 values below 10 nM. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, v-Abl and serine/threonine kinases (PKC alpha, CDK1) was observed. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 15, 19, 22, and 23 at IC50 values below 50 nM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 microM, thus indicating high selectivity for the inhibition of the ligand-activated EGF-R signal transduction pathway. Compounds 15 and 19 inhibited proliferation of the EGF-dependent MK cell line with IC50 values below 0.5 microM. In addition, two compounds, 9 and 11, showing satisfactory oral bioavailability in mice after oral administration, exhibited good in vivo efficacy at doses of 12.5 and 50 mg/kg in a nude mouse tumor model using xenografts of the EGF-R overexpressing A431 cell line. From SAR studies, a binding mode for 4-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidines, especially for compound 15, at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)-1H-pyrazolo[3,4-d]pyrimidines represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.
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PMID:Use of a pharmacophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(phenylamino)pyrazolo[3,4-d]pyrimidines. 935 27

In contrast to the situation for genotoxic carcinogens, few in vitro tests exist that can detect early markers of the events thought to be associated with non-genotoxic carcinogenesis. Also, comparatively little is known about the quantitative structure-activity relationships (Q)SARs of these agents. This review discusses published SAR studies conducted on non-genotoxic carcinogens, in relation to the use of several markers of in vitro cell toxicity (inhibition of gap-junctional intercellular communication, inhibition of tubulin polymerization, modulation of apoptosis and induction of cell proliferation), which are used as endpoints for screening this class of carcinogen. Much of the work has involved the identification of new biophores (substructural features of molecules associated with toxicity), as well as other structural features, which are thought to predispose the chemicals to ligand binding with specific target molecules acting as possible receptors (e.g. protein kinase C, the oestrogen, peroxisome-proliferator and tubulin protein receptors), implicated in the mechanism of toxicity involved. It is concluded that (a) there is an urgent need for more information on (Q)SARs for non-genotoxic carcinogens; (b) this information should be acquired by using several different approaches in a variety of laboratories; and (c) such research should proceed together with more studies on the mechanisms of cell toxicity caused by these chemicals, including the identification and characterisation of further specific receptors involved in mediating the various types of cell toxicity associated with this type of carcinogenesis.
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PMID:The use of structure-activity relationships and markers of cell toxicity to detect non-genotoxic carcinogens. 1090 45

Polychlorinated biphenyls (PCBs) are persistent, bioaccumulative, toxic, and widely distributed environmental chemicals. There is now both epidemiological and experimental evidence that PCBs cause cognitive deficits; however, the underlying cellular or molecular mechanism(s) is not known. We have hypothesized that altered signal transduction/second messenger homeostasis by PCBs may be associated with these effects since second messengers in signal transduction pathways, such as calcium, inositol phosphates (IP), and protein kinase C (PKC), play key roles in neuronal development and their function. In vitro studies using cerebellar granule neurons and isolated organelle preparations indicate that ortho-PCBs increase intracellular free Ca2+ levels by inhibiting microsomal and mitochondrial Ca2+ buffering and the Ca2+ extrusion process. Ortho-PCBs also increase agonist-stimulated IP accumulation and cause PKC translocation at low micromolar concentrations where no cytotoxicity is observed. On the other hand, non-ortho-PCBs are not effective in altering these events. Further SAR studies indicate that congeners with chlorine substitutions favoring non-coplanarity are active in vitro, while congeners favoring coplanarity are relatively inactive. Subsequent in vivo studies have shown that repeated exposure to a PCB mixture, Aroclor 1254, increases PKC translocation and decreases Ca2+ buffering in the brain, similar to in vitro studies. These changes in vivo are associated with elevated levels of non-coplanar ortho-PCB congeners at levels equivalent to 40-50 microM in brain, the concentrations that significantly inhibited second messenger systems in neuronal cultures in vitro. Current research is focusing on PCB-induced alterations in second messenger systems following developmental exposure.
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PMID:Neurochemical effects of environmental chemicals: in vitro and in vivo correlations on second messenger pathways. 1108 2

The present work describes the effect of amplitude modulated radio frequency (rf) radiation (112 MHz amplitude-modulated at 16 Hz) on calcium-dependent protein kinase C (PKC) activity on developing rat brain. Thirty-five days old Wistar rats were used for this study. The rats were exposed 2 h per day for 35 days at a power density of 1.0 mW/cm2 (SAR = 1.48 W/kg). After exposure, rats were sacrificed and PKC was determined in whole brain, hippocampus and whole brain minus hippocampus separately. A significant decrease in the enzyme level was observed in the exposed group as compared to the sham exposed group. These results indicate that this type of radiation could affect membrane bound enzymes associated with cell signaling, proliferation and differentiation. This may also suggest an affect on the behavior of chronically exposed rats.
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PMID:Radio frequency radiation effects on protein kinase C activity in rats' brain. 1469 22

Abrogation of mitochondrial permeability and induction of reactive oxygen species (ROS) production have been observed in chemical-induced apoptosis; however, the relationship between the mitochondria and intracellular ROS levels in apoptosis is still unclear. In the present study, myricetin (ME) but not its respective glycoside, myricitrin (MI; myricetin-3-O-rhamnose) reduced the viability of human leukemia HL-60 cells via apoptosis, characterized by the occurrence of DNA ladders and hypodiploid cells. Results of Western blotting and caspase activity assays showed that activation of caspases 3 and 9 but not caspases 1, 6 or 8 with cleavage of PARP and D4-GDI proteins is involved in ME-induced apoptosis. A reduction in mitochondrial functions characterized by a decrease in the Bcl-2/Bax protein ratio and translocation of cytochrome c (cyt c) from the mitochondria to the cytosol in accordance with a decrease in mitochondrial membrane potential were observed in ME-treated HL-60 cells. No significant induction of intracellular ROS levels by ME was observed by the DCHF-DA assay, DPPH assay or plasmid digestion assay, and antioxidants including N-acetyl-cysteine (NAC), catalase (CAT), superoxide dismutase (SOD), and tiron (TIR) showed no protective effects on ME-induced apoptosis. A PKC activator, 12-O-tetradecaoylphorbol-13-acetate (TPA) significantly attenuated ME-induced apoptosis via preventing cytochrome c release to the cytosol and maintaining the mitochondrial membrane potential by inhibiting the decrease in the Bcl-2/Bax protein ratio; these effects were blocked by protein kinase C (PKC) inhibitors including GF-109203X, H7, and staurosporin. Removing mitochondria by ethidium bromide (EtBr) treatment reduced the apoptotic effect of ME. Results of SAR studies showed that the presence of OH at C3', C4', and C5' is important for the apoptosis-inducing activities of ME, and that ME induces apoptosis in another leukemia cell line, Jurkat cells, but not in primary human polymorphonuclear (PMN) cells or in murine peritoneal macrophages (PMs). The results of the present study suggest that apoptosis induced by ME occurs through a novel mitochondrion-dependent, ROS-independent pathway; TPA protects cells from ME-induced apoptosis via PKC activation which prevents the occurrence of mitochondrial destruction during apoptosis.
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PMID:Mitochondrial-dependent, reactive oxygen species-independent apoptosis by myricetin: roles of protein kinase C, cytochrome c, and caspase cascade. 1574 3

A novel, short, and efficient synthetic pathway to 3-{4-[2-(3-chlorophenylamino)-pyrimidin-4-yl]-pyridin-2-ylamino}-propanol (CGP 60474) and a series of analogues was developed. The synthetic sequence consisted of a Negishi-type cross-coupling reaction in the key step followed by two subsequent nucleophilic substitution reactions. This strategy represents a versatile and robust protocol to access diverse analogues of the title compound for subsequent SAR studies as potential phenylamino-pyrimidine type protein kinase C inhibitors.
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PMID:Novel and efficient access to phenylamino-pyrimidine type protein kinase C inhibitors utilizing a Negishi cross-coupling strategy. 1596 May 26

There is growing concern by the public regarding the potential human health hazard due to exposure to microwave frequencies. 2.45 GHz radiation widespread use in industry, research, and medicine, and leakage into the environment is possible. In order to quantitate this, experiments were performed on developing rat brain. Male Wistar 35-day-old rats (n = 6) were used for this study. Animals were exposed to 2.45 GHz radiation for 2 h/day for a period of 35 days at a power density of 0.344 mW/cm(2) (SAR 0.11 W/kg). The control group was sham irradiated. After 35 days these rats were sacrificed and whole brain tissue was isolated for protein kinase C (PKC) assay. For morphological study the forebrain was isolated from the whole brain and PKC activity was measured using P(32) labeled ATP. Our study reveals a statistically significant (p < 0.05) decrease in PKC activity in hippocampus as compared to the remaining portion of the whole brain and the control group. A similar experiment conducted on hippocampus and the whole brain gave a similar result. Electron microscopic study shows an increase in the glial cell population in the exposed group as compared to the control group. This present study is indicative of a significant change after exposure to the above-mentioned field intensity. This suggests that chronic exposures may affect brain growth and development.
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PMID:Protein kinase C activity in developing rat brain cells exposed to 2.45 GHz radiation. 1659 35


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