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1.
Bioorg Med Chem Lett ; 27(18): 4370-4376, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28830649

RESUMO

Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.


Assuntos
Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , TYK2 Quinase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , TYK2 Quinase/metabolismo
2.
Proc Natl Acad Sci U S A ; 111(22): 8025-30, 2014 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-24843152

RESUMO

Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase-kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and "exon 12" JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state.


Assuntos
Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Janus Quinase 3/metabolismo , Neoplasias/enzimologia , Transdução de Sinais/fisiologia , TYK2 Quinase/metabolismo , Animais , Linhagem Celular , Cristalografia por Raios X , Dimerização , Ativação Enzimática/fisiologia , Humanos , Insetos/citologia , Janus Quinase 1/genética , Janus Quinase 2/genética , Janus Quinase 3/genética , Mutação , Neoplasias/genética , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , TYK2 Quinase/química , TYK2 Quinase/genética
3.
Cell Death Differ ; 27(1): 161-175, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31101885

RESUMO

The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis and necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases. Here, we explore the effect of inhibiting RIP1 genetically, using knock-in mice that express catalytically inactive RIP1 D138N, or pharmacologically, using the murine-potent inhibitor GNE684. Inhibition of RIP1 reduced collagen antibody-induced arthritis, and prevented skin inflammation caused by mutation of Sharpin, or colitis caused by deletion of Nemo from intestinal epithelial cells. Conversely, inhibition of RIP1 had no effect on tumor growth or survival in pancreatic tumor models driven by mutant Kras, nor did it reduce lung metastases in a B16 melanoma model. Collectively, our data emphasize a role for the kinase activity of RIP1 in certain inflammatory disease models, but question its relevance to tumor progression and metastases.


Assuntos
Inflamação/enzimologia , Neoplasias/enzimologia , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Animais , Artrite/enzimologia , Morte Celular , Linhagem Celular , Linhagem Celular Tumoral , Colite/etiologia , Colite/prevenção & controle , Dermatite/enzimologia , Feminino , Técnicas de Introdução de Genes , Humanos , Ileíte/etiologia , Ileíte/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Melanoma Experimental/patologia , Camundongos , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ratos , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/fisiologia
4.
J Med Chem ; 56(11): 4764-85, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23659214

RESUMO

Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.


Assuntos
Antirreumáticos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Imidazóis/síntese química , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Piridinas/síntese química , Pirróis/síntese química , Administração Oral , Animais , Antirreumáticos/química , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/etiologia , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Colágeno , Cristalografia por Raios X , Cães , Haplorrinos , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Janus Quinase 1/química , Janus Quinase 2/química , Células Madin Darby de Rim Canino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Ratos , Estereoisomerismo
5.
J Med Chem ; 55(12): 5901-21, 2012 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-22591402

RESUMO

A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.


Assuntos
Imidazóis/química , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Linhagem Celular , Janus Quinase 1/química , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/química , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Especificidade por Substrato
6.
J Med Chem ; 55(13): 6176-93, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22698084

RESUMO

Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.


Assuntos
Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Animais , Bioensaio , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Cães , Hepatócitos/citologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Janus Quinase 1/química , Janus Quinase 2/química , Camundongos , Modelos Moleculares , Ratos , Relação Estrutura-Atividade
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