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1.
J Med Chem ; 49(15): 4455-8, 2006 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-16854050

RESUMO

C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of inhibiting these enzymes and as leads for potential drugs targeting JNKs. In this report, we disclose a series of potent and highly selective JNK inhibitors with good pharmacokinetic profiles.


Assuntos
Amidas/síntese química , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Piridinas/síntese química , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Termodinâmica
2.
Biochem Biophys Res Commun ; 343(2): 361-8, 2006 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-16545776

RESUMO

Activation of PKCtheta is associated with lipid-induced insulin resistance and PKCtheta knockout mice are protected from the lipid-induced defects. However, the exact mechanism by which PKCtheta contributes to insulin resistance is not known. To investigate whether an increase in PKCtheta expression leads to insulin resistance, C2C12 skeletal muscle cells were transfected with PKCtheta DNA and treated with different concentrations of insulin for 10 min. PKCtheta overexpression induced reduction of IRS-1 protein levels with a decrease in insulin-induced p85 binding to IRS-1, phosphorylation of PKB and its substrates, p70 and GSK3. Pretreatment of these cells with GF-109203X (a non-specific PKC inhibitor, IC50 for PKCtheta = 10 nM) recovered insulin signaling. PKCtheta was found to be expressed in liver and treatment of human hepatoma cells (HepG2) with high insulin and glucose resulted in an increase in PKCtheta expression that correlated with a decrease in IRS-1 protein levels and the development of insulin resistance. Reduction of PKCtheta expression using RNAi technology significantly inhibited the degradation of IRS-1 and enhanced insulin-induced IRS-1 tyrosine phosphorylation, p85 association to IRS-1 and PKB phosphorylation. In conclusion, by overexpressing PKCtheta or using RNAi technology to downregulate PKCtheta, we have demonstrated that PKCtheta has a key role in the development of insulin resistance. These findings suggest that PKCtheta mediates not only insulin resistance in muscle but also in liver, which may contribute to the development of whole body insulin resistance and diabetes.


Assuntos
Resistência à Insulina/fisiologia , Insulina/administração & dosagem , Isoenzimas/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Proteína Quinase C/metabolismo , Transdução de Sinais/fisiologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Mioblastos , Proteína Quinase C-theta , Transdução de Sinais/efeitos dos fármacos
3.
Peptides ; 25(7): 1171-8, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15245877

RESUMO

The glucagon receptor was cloned from cynolomologous monkey. A frame-shift mutation at the 3' end of the monkey transcript results in a C-terminal extension of 14 amino acids. This extension is not observed in either the human or rodent glucagon receptors. Monkey glucagon receptor was expressed in CHO cells, either with (mkGCGR) or without (mkGCGRDelta14) the 14-amino acid C-terminal extension to approximate the human receptor. Both forms of the monkey receptor bound glucagon with similar affinity and showed glucagon-stimulated cAMP production, however the full-length form of the monkey receptor (mkGCGR) was less sensitive to glucagon in its ability to stimulate cAMP than the shortened form (mkGCGRDelta14). PCR of genomic DNA from baboon and rhesus monkeys suggests that they express a form of the receptor similar to that of cynomologous monkey, while in chimpanzee, the receptor is similar to the human form.


Assuntos
Haplorrinos/genética , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Animais , Sequência de Bases , Células CHO , Clonagem Molecular , Cricetinae , AMP Cíclico/metabolismo , DNA Complementar/genética , Glucagon/metabolismo , Humanos , Dados de Sequência Molecular , RNA/genética , Receptores de Glucagon/química , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico
4.
J Biomol Screen ; 8(6): 668-75, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14711392

RESUMO

In micro-arrayed compound screening (microARCS), an agarose gel is used as a reaction vessel that maintains humidity and compound location as well as being a handling system for reagent addition. Two or more agarose gels may be used to bring test compounds, targets, and reagents together, relying on the pore size of the gel matrix to regulate diffusion of reactants. It is in the microenvironment of the agarose matrix that all the components of an enzymatic reaction interact and result in inhibitable catalytic activity. In an effort to increase the throughput of microARCS-based screens, reduce the effort involved in manipulating agarose gels, and reduce costs, blotter paper was used rather than a second agarose gel to introduce a substrate to a gel containing a target enzyme. In this assay, the matrix of the blotter paper did not prevent the substrate from diffusing into the enzyme gel. The compound density of the microARCS format, the ease of manipulating sheets of paper for reagent addition, and a scheduled protocol for running multiple gels allowed for a throughput capacity of more than 200,000 tests per hour. A protease assay was developed and run in the microARCS format at a rate of 200,000 tests per hour using blotter paper to introduce the substrate. Picks in the primary screen were retested in the microARCS format at a density of 384 compounds per sheet. IC(50) values were confirmed in a 96-well plate format. The screen identified several small molecule inhibitors of the enzyme. The details of the screening format and the analysis of the hits from the screen are presented.


Assuntos
Endopeptidases/metabolismo , Análise Serial de Proteínas/métodos , Células CACO-2 , Dimetil Sulfóxido/farmacologia , Humanos , Umidade , Concentração Inibidora 50 , Inibidores de Proteases/farmacologia , Sefarose , Especificidade por Substrato
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