Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
Oncogene ; 35(17): 2197-207, 2016 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-26257057

RESUMO

Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Proteínas de Membrana/genética , Proteínas Wnt/genética , Aciltransferases , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Processamento de Proteína Pós-Traducional , Células-Tronco/efeitos dos fármacos , Proteínas Wnt/antagonistas & inibidores , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Chem Pharm Bull (Tokyo) ; 49(8): 1009-17, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11515569

RESUMO

Structure activity studies of N-phenylrolipram derivatives have led to the identification of highly potent PDE4 inhibitors. The potential of these inhibitors for cellular activity was routinely assessed in an assay of fMLP induced oxidative burst in human eosinophils. Since first generation PDE4 inhibitors have been plagued with a number of unwanted side effects, parallel structure activity studies for competition with the [3H]-rolipram binding site in rat brain were performed. In this fashion 5-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]-3-(3-methoxybenzyloxy)benzoic acid N',N'-dimethylhydrazide (22) was identified as a potent inhibitor of PDE4 which exhibits >1000 fold selectivity versus PDE3, and is a nanomolar inhibitor in all the cellular assays tested. Studies on the stereoselectivity of PDE4 inhibition of this class of rolipram based compounds revealed, that for example (S)-11 is a more potent inhibitor than (R)-11. This effect can also be observed in primary human cells where the (S)-enantiomer is about 10 fold more potent than the corresponding (R)-enantiomer.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores de Fosfodiesterase/farmacologia , Rolipram/análogos & derivados , Rolipram/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Encéfalo/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Eosinófilos/efeitos dos fármacos , Eosinófilos/enzimologia , Eosinófilos/metabolismo , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Inibidores de Fosfodiesterase/química , Ratos , Explosão Respiratória/efeitos dos fármacos , Explosão Respiratória/fisiologia , Rolipram/química , Estereoisomerismo , Relação Estrutura-Atividade
3.
ANNA J ; 26(3): 307-16; discussion 317, 335, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10633602

RESUMO

The purpose of this study was to describe the prevalence, severity, and patterns of noncompliance with prescribed medications among hemodialysis patients; and to identify patient, disease and/or treatment characteristics associated with noncompliance. Demographic and medical history information were collected from chart reviews and patient interviews. Compliance data were collected via self-report, pill count, and a medication event monitoring system (MEMS, Product of Aprex, a division of Apria Healthcare; Costa Mesa, CA). A total of 135 hemodialysis patients from 11 dialysis facilities in a large Midwestern metropolitan area participated. Overall, medication compliance rates were very low. Of the patient, disease, and treatment characteristics considered, only race was found to be associated with patient noncompliance; African-American patients had higher rates of noncompliance with both monitored medications. The results of this study confirm that noncompliance with medication regimens continues to be an unremitting problem for hemodialysis patients and that demographic, medical history, and treatment characteristics do not adequately explain this behavior. Also, estimates of patient compliance as measured by self-report, pill count, and microelectronic monitoring are disparate enough to suggest that relying exclusively on patients' self-report of compliance might be insufficient.


Assuntos
Anti-Hipertensivos/uso terapêutico , Falência Renal Crônica/psicologia , Falência Renal Crônica/terapia , Cooperação do Paciente/psicologia , Cooperação do Paciente/estatística & dados numéricos , Diálise Renal/psicologia , Autoadministração/psicologia , Autoadministração/estatística & dados numéricos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Monitoramento de Medicamentos , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Erros de Medicação/psicologia , Erros de Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Prevalência , Fatores de Risco
4.
Biophys J ; 74(4): 2076-9, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9545066

RESUMO

Scanning near-field optical microscopy can provide images with a resolution less than the wavelength of light, and therefore ought in principle to be of great value in studies of biological structures. In this work we show how for the first time images have been obtained of tobacco mosaic virus particles at 60-nm resolution, combined with chemical imaging using monoclonal antibodies under in vitro conditions.


Assuntos
Vírus do Mosaico do Tabaco/química , Vírus do Mosaico do Tabaco/ultraestrutura , Anticorpos Monoclonais , Anticorpos Antivirais , Fenômenos Biofísicos , Biofísica , Microscopia/métodos , Microscopia de Força Atômica , Óptica e Fotônica , Soluções , Vírus do Mosaico do Tabaco/imunologia
5.
Bioorg Med Chem Lett ; 8(22): 3229-34, 1998 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-9873708

RESUMO

Derivatization of rolipram led to the identification of 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]-5-( 3- methoxybenzyloxy)-benzoic acid N',N'-dimethylhydrazide (4), a potent and selective inhibitor of PDE4, which inhibits the activation of human leukocytes with pIC50 values in the range of 7.3-7.8, and blocks antigen induced eosinophilia in Brown Norway rats at a dose of 1 mg/kg (i.t.).


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Antiasmáticos/síntese química , Inibidores de Fosfodiesterase/síntese química , Pirrolidinonas/síntese química , Animais , Antiasmáticos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Humanos , Leucócitos/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Pirrolidinonas/farmacologia , Ratos , Ratos Endogâmicos BN , Rolipram , Relação Estrutura-Atividade
6.
J Mol Biol ; 246(2): 344-55, 1995 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-7532720

RESUMO

Src homology-2 (SH2) domains are protein modules found within a wide variety of cytoplasmic signalling molecules that bind with high affinity to phosphotyrosyl-containing protein sequences. In order to develop SH2 inhibitors that contain phosphotyrosyl analogues resistant to cellular phosphatases, we have solved the crystal structures of the SH2 domain of p56lck in separate complexes with two high-affinity p-(phosphonomethyl)phenylalanine-containing peptides. The structures have been determined at 2.3 A and 2.25 A, and refined to crystallographic R-factors of 19.2% and 18.5%, respectively. The conformation of the SH2 domain of p56lck is essentially similar to that observed in Src and Lck complexed with a phosphotyrosine-containing peptide except in some loops and especially in the loop that connects the second and third beta-strands. This loop, which was involved in hydrogen-bond interactions with the phosphotyrosine moiety, has moved away in the phosphonopeptide complexes as a rigid body by about 7 A on two hinges leaving the tyrosine phosphate mimetic moiety accessible to the solvent. Some intramolecular hydrogen bonds with other residues of the third and fourth beta-strands stabilize an open conformation of the lid, suggesting a flap mechanism for peptide binding.


Assuntos
Peptídeos/química , Fenilalanina/análogos & derivados , Conformação Proteica , Estrutura Secundária de Proteína , Proteínas Tirosina Quinases/química , Sequência de Aminoácidos , Animais , Sítios de Ligação , Cristalografia por Raios X , Proteína Tirosina Quinase p56(lck) Linfócito-Específica , Linfócitos/enzimologia , Modelos Moleculares , Dados de Sequência Molecular , Peptídeos/síntese química , Peptídeos/metabolismo , Fosfotirosina , Ligação Proteica , Proteínas Tirosina Quinases/metabolismo , Tirosina/análogos & derivados
8.
Nucleic Acids Res ; 21(19): 4499-505, 1993 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-8233783

RESUMO

A versatile, general way is described for the introduction of different functional groups into oligonucleotides by means of a simple linker at the 2'-position of the sugar. Nucleotide building blocks carrying lipophilic, intercalating or tertiary amino groups can be placed deliberately at any desired position of oligonucleotides by standard automated oligonucleotide synthesis. Thermal denaturation studies with these oligonucleotides reveal the following general trends: i) Modification with lipophilic n-octyl groups has little if any effect on duplex stability; a destabilizing (lipophilic) substituent is better tolerated at or near the ends than in the middle of the oligo. ii) An intercalating substituent (2-aminoanthraquinone) substantially increases duplex stability. iii) N,N-Dimethyl amino residues also increase duplex stability though to a smaller extent than intercalating residues. iv) Modifications at the 5'-end have a more pronounced influence on the TM than the corresponding 3'-modifications. v) Oligonucleotides modified in such a way show little or no loss in sequence specificity.


Assuntos
Oligorribonucleotídeos/química , Desnaturação de Ácido Nucleico , Hibridização de Ácido Nucleico , Relação Estrutura-Atividade
9.
Biochem Biophys Res Commun ; 176(1): 401-5, 1991 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-2018529

RESUMO

The binding properties and limitations of the key S1 site of subtilisin Carlsberg have been probed with boronic acid inhibitors bearing structurally varied substituents ranging from small alkyl to large aromatic groups. The data permit structural features favoring, and disfavoring, good S1 binding to be clarified. In addition, applications of electrostatic energy calculations have identified a hitherto unsuspected region of positive potential in the fundamentally hydrophobic S1 pocket, whose interactions with electronegative substituents of inhibitors can make significant binding contributions.


Assuntos
Ácidos Borônicos/farmacologia , Subtilisinas/metabolismo , Sítios de Ligação , Cinética , Relação Estrutura-Atividade , Subtilisinas/antagonistas & inibidores
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA