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










Base de dados
Intervalo de ano de publicação
1.
J Med Chem ; 63(2): 601-612, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31859507

RESUMO

The serine/threonine kinase TBK1 (TANK-binding kinase 1) and its homologue IKKε are noncanonical members of the inhibitor of the nuclear factor κB (IκB) kinase family. These kinases play important roles in multiple cellular pathways and, in particular, in inflammation. Herein, we describe our investigations on a family of benzimidazoles and the identification of the potent and highly selective TBK1/IKKε inhibitor BAY-985. BAY-985 inhibits the cellular phosphorylation of interferon regulatory factor 3 and displays antiproliferative efficacy in the melanoma cell line SK-MEL-2 but showed only weak antitumor activity in the SK-MEL-2 human melanoma xenograft model.


Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Modelos Moleculares , Fosforilação , Relação Estrutura-Atividade , Especificidade por Substrato
2.
Clin Cancer Res ; 25(4): 1404-1414, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30429199

RESUMO

PURPOSE: The catalytic function of BUB1 is required for chromosome arm resolution and positioning of the chromosomal passenger complex for resolution of spindle attachment errors and plays only a minor role in spindle assembly checkpoint activation. Here, we present the identification and preclinical pharmacologic profile of the first BUB1 kinase inhibitor with good bioavailability. EXPERIMENTAL DESIGN: The Bayer compound library was screened for BUB1 kinase inhibitors and medicinal chemistry efforts to improve target affinity and physicochemical and pharmacokinetic parameters resulting in the identification of BAY 1816032 were performed. BAY 1816032 was characterized for kinase selectivity, inhibition of BUB1 signaling, and inhibition of tumor cell proliferation alone and in combination with taxanes, ATR, and PARP inhibitors. Effects on tumor growth in vivo were evaluated using human triple-negative breast xenograft models. RESULTS: The highly selective compound BAY 1816032 showed long target residence time and induced chromosome mis-segregation upon combination with low concentrations of paclitaxel. It was synergistic or additive in combination with paclitaxel or docetaxel, as well as with ATR or PARP inhibitors in cellular assays. Tumor xenograft studies demonstrated a strong and statistically significant reduction of tumor size and excellent tolerability upon combination of BAY 1816032 with paclitaxel or olaparib as compared with the respective monotherapies. CONCLUSIONS: Our findings suggest clinical proof-of-concept studies evaluating BAY 1816032 in combination with taxanes or PARP inhibitors to enhance their efficacy and potentially overcome resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HeLa , Humanos , Camundongos , Neoplasias/genética , Neoplasias/patologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Taxoides/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Elife ; 52016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26885717

RESUMO

The kinase Bub1 functions in the spindle assembly checkpoint (SAC) and in chromosome congression, but the role of its catalytic activity remains controversial. Here, we use two novel Bub1 inhibitors, BAY-320 and BAY-524, to demonstrate potent Bub1 kinase inhibition both in vitro and in intact cells. Then, we compared the cellular phenotypes of Bub1 kinase inhibition in HeLa and RPE1 cells with those of protein depletion, indicative of catalytic or scaffolding functions, respectively. Bub1 inhibition affected chromosome association of Shugoshin and the chromosomal passenger complex (CPC), without abolishing global Aurora B function. Consequently, inhibition of Bub1 kinase impaired chromosome arm resolution but exerted only minor effects on mitotic progression or SAC function. Importantly, BAY-320 and BAY-524 treatment sensitized cells to low doses of Paclitaxel, impairing both chromosome segregation and cell proliferation. These findings are relevant to our understanding of Bub1 kinase function and the prospects of targeting Bub1 for therapeutic applications.


Assuntos
Cromossomos Humanos/metabolismo , Inibidores Enzimáticos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Linhagem Celular , Humanos
4.
Exp Dermatol ; 20(1): 41-7, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21158938

RESUMO

T-cell-mediated processes play an essential role in the pathogenesis of several inflammatory skin diseases such as atopic dermatitis, allergic contact dermatitis and psoriasis. The aim of this study was to investigate the role of the IL-2-inducible tyrosine kinase (Itk), an enzyme acting downstream of the T-cell receptor (TCR), in T-cell-dependent skin inflammation using three approaches. Itk knockout mice display significantly reduced inflammatory symptoms in mouse models of acute and subacute contact hypersensitivity (CHS) reactions. Systemic administration of a novel small molecule Itk inhibitor, Compound 44, created by chemical optimization of an initial high-throughput screening hit, inhibited Itk's activity with an IC50 in the nanomolar range. Compound 44 substantially reduced proinflammatory immune responses in vitro and in vivo after systemic administration in two acute CHS models. In addition, our data reveal that human Itk, comparable to its murine homologue, is expressed mainly in T cells and is increased in lesional skin from patients with atopic dermatitis and allergic contact dermatitis. Finally, silencing of Itk by RNA interference in primary human T cells efficiently blocks TCR-induced lymphokine secretion. In conclusion, Itk represents an interesting new target for the therapy of T-cell-mediated inflammatory skin diseases.


Assuntos
Dermatite/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Sequência de Bases , Dermatite/enzimologia , Dermatite/imunologia , Dermatite Alérgica de Contato/tratamento farmacológico , Dermatite Alérgica de Contato/enzimologia , Dermatite Alérgica de Contato/imunologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/enzimologia , Dermatite Atópica/imunologia , Dinitroclorobenzeno/imunologia , Dinitroclorobenzeno/toxicidade , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Perfilação da Expressão Gênica , Humanos , Técnicas In Vitro , Tecido Linfoide/enzimologia , Tecido Linfoide/imunologia , Camundongos , Camundongos Knockout , Proteínas Tirosina Quinases/deficiência , Proteínas Tirosina Quinases/genética , Psoríase/tratamento farmacológico , Psoríase/enzimologia , Psoríase/imunologia , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Proteínas Recombinantes de Fusão/antagonistas & inibidores , Proteínas Recombinantes de Fusão/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia , Linfócitos T/imunologia , Regulação para Cima
5.
J Invest Dermatol ; 130(2): 481-91, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19657354

RESUMO

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a downstream molecule of p38, involved in the production of TNF-alpha, a key cytokine, and an established drug target for many inflammatory diseases. We investigated the role of MK2 in skin inflammation to determine its drug target potential. MK2 deficiency significantly decreased plasma TNF-alpha levels after systemic endotoxin application. Deficient mice showed decreased skin edema formation in chronic 2-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritative dermatitis and in subacute 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity. Surprisingly, MK2 deficiency did not inhibit edema formation in subacute 2,4-dinitrochlorobenzene (DNCB)-induced contact allergy and even increased TNF-alpha and IL-1beta levels as well as granulocyte infiltration in diseased ears. Ear inflammation in this model, however, was inhibited by TNF-alpha neutralization as it was in the subacute DNFB model. MK2 deficiency also did not show anti-inflammatory effects in acute DNFB-induced contact hypersensitivity, whereas the p38 inhibitor, SB203580, ameliorated skin inflammation supporting a pathophysiological role of p38. When evaluating possible mechanisms, we found that TNF-alpha production in MK2-deficient spleen cells was strongly diminished after TLR stimulation but less affected after T-cell receptor stimulation. Our data suggest that MK2, in contrast to its downstream effector molecule, TNF-alpha, has a rather elusive role in T-cell-dependent cutaneous inflammation.


Assuntos
Inflamação , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Pele/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Dermatite de Contato , Dinitrofluorbenzeno/química , Feminino , Granulócitos/citologia , Homozigoto , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/metabolismo , Pele/enzimologia , Acetato de Tetradecanoilforbol/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
6.
Bioorg Med Chem Lett ; 18(22): 5975-7, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18682325

RESUMO

5-Aminovaleric acid and ornithine were evaluated as linkers for the cyclization of beta-dipeptides. Two linked examples of beta-Ala-beta-Ala were prepared by standard coupling methods and their conformations probed by NMR, CD, and computational means. The data suggest that these non- or monosubstituted versions of the target compounds are flexible in solution.


Assuntos
Alanina/análogos & derivados , Alanina/síntese química , Aminoácidos Neutros/síntese química , Dipeptídeos/química , Dipeptídeos/síntese química , Peptídeos Cíclicos/química , Aminoácidos Neutros/química , Ciclização , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Ornitina/farmacologia
7.
J Mol Biol ; 369(3): 735-45, 2007 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-17449059

RESUMO

The Ser/Thr protein kinase MAPKAP kinase 2 (MK2) plays a crucial role in inflammation. We determined the structure of the kinase domain of MK2 in complex with a low molecular mass inhibitor in two different crystal forms, obtained from soaking and co-crystallization. To our knowledge, these are the first structures of MK2 showing the binding mode of an inhibitor with high binding affinity (IC50 8.5 nM). The two crystal forms revealed conformational flexibility in the binding site and extend the experimental basis for rational drug design. Crystal form-1 contained one MK2 molecule per asymmetric unit. Form-2 contained 12 molecules, which arrange into two different types of MK2 trimers. One of them may serve as a model for an intermediate state during substrate phosphorylation, as each MK2 monomer places its activation segment into the substrate peptide binding groove of the trimer neighbor.


Assuntos
Inibidores Enzimáticos/química , Proteínas Quinases/química , Trifosfato de Adenosina/química , Sequência de Aminoácidos , Sítios de Ligação , Cristalização , Dimerização , Desenho de Fármacos , Elétrons , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular , Modelos Moleculares , Conformação Molecular , Dados de Sequência Molecular , Ligação Proteica , Conformação Proteica , Proteínas Serina-Treonina Quinases
8.
Bioorg Med Chem Lett ; 14(7): 1673-7, 2004 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-15026048

RESUMO

Based on molecular modeling studies, macrocyclic inhibitors of phosphatase cdc25B were synthetically derived from steroids. A preliminary SAR for this new template was elaborated. A series of compounds shows inhibition of cdc25B in the low micromolar range and good selectivity versus other phosphatases. The compounds did not show a significant antiproliferative effect in MaTu or HaCaT cells.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteases/síntese química , Fosfatases cdc25/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Inibidores de Proteases/metabolismo , Relação Estrutura-Atividade , Fosfatases cdc25/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA