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1.
Mini Rev Med Chem ; 19(18): 1531-1543, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31288716

RESUMO

The search for inhibitors of the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) has been ongoing for several decades and has resulted in a number of JAK inhibitors being approved for use in patients, such as tofacitinib for the treatment of autoimmune diseases such as Rheumatoid Arthritis (RA). Although initially thought to be a JAK3 selective inhibitor, tofacitinib was subsequently found to possess significant activity to inhibit JAK1 and JAK2 which has contributed to some adverse side effects. A selective JAK3 inhibitor should only have an effect within the immune system since JAK3 is solely expressed in lymphoid tissue; this makes JAK3 a target of interest in the search for treatments of autoimmune diseases. A method to obtain selectivity for JAK3 over the other JAK family members, which has attracted more scientific attention recently, is the targeting of the active site cysteine residue, unique in JAK3 within the JAK family, with compounds containing electrophilic warheads which can form a covalent bond with the nucleophilic thiol of the cysteine residue. This review encompasses the historical search for a covalent JAK3 inhibitor and the most recently published research which hasn't been reviewed to date. The most important compounds from the publications reviewed the activity and selectivity of these compounds together with some of the more important biological results are condensed in to an easily digested form that should prove useful for those interested in the field.


Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Amidas/química , Amidas/metabolismo , Amidas/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Derivados de Benzeno/química , Derivados de Benzeno/metabolismo , Derivados de Benzeno/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Janus Quinase 3/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico
2.
ACS Chem Biol ; 14(6): 1235-1242, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31082193

RESUMO

PF-06651600 was developed as an irreversible inhibitor of JAK3 with selectivity over the other three JAK isoforms. A high level of selectivity toward JAK3 is achieved by the covalent interaction of PF-06651600 with a unique cysteine residue (Cys-909) in the catalytic domain of JAK3, which is replaced by a serine residue in the other JAK isoforms. Importantly, 10 other kinases in the kinome have a cysteine at the equivalent position of Cys-909 in JAK3. Five of those kinases belong to the TEC kinase family including BTK, BMX, ITK, RLK, and TEC and are also inhibited by PF-06651600. Preclinical data demonstrate that inhibition of the cytolytic function of CD8+ T cells and NK cells by PF-06651600 is driven by the inhibition of TEC kinases. On the basis of the underlying pathophysiology of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, alopecia areata, and vitiligo, the dual activity of PF-06651600 toward JAK3 and the TEC kinase family may provide a beneficial inhibitory profile for therapeutic intervention.


Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Lectinas Tipo C/antagonistas & inibidores , Lectinas Tipo C/imunologia , Camundongos
3.
Expert Rev Clin Pharmacol ; 12(6): 547-554, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059310

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by synovitis as well as symmetric and destructive arthropathy. Although several disease modified antirheumatic-drugs (DMARDs) have widely used in clinical practice, certain patients are nonresponsive to or cannot take such medications due to adverse reactions. It is evident that Janus kinase (JAK) inhibitors have the potential to provide a significant breakthrough in the treatment of RA. These potent, orally administered, JAK inhibitors simplify the treatment options for patients. Areas covered: We discuss the pharmacodynamics, pharmacokinetics, efficacy, and safety of peficitinib for the treatment of RA. Expert opinion: Peficitinib is a novel JAK3 inhibitor potently inhibiting JAK3 enzymatic activity and JAK1/3-mediated cell proliferation. Its selectivity for JAK family kinases is similar to that of tofacitinib, but slightly less potent for JAK2. It is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate. It can be used either as monotherapy or combination therapy with methotrexate, or other DMARDs. However, we think that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Niacinamida/análogos & derivados , Adamantano/efeitos adversos , Adamantano/farmacologia , Adamantano/uso terapêutico , Adulto , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/enzimologia , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinase 3/antagonistas & inibidores , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico
4.
Immunity ; 50(4): 832-850, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995502

RESUMO

The common cytokine receptor γ chain, γc, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γc results in X-linked severe combined immunodeficiency in humans, and γc family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.


Assuntos
Citocinas/classificação , Subunidade gama Comum de Receptores de Interleucina/genética , Família Multigênica/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Citocinas/genética , Citocinas/imunologia , Evolução Molecular , Regulação da Expressão Gênica , Terapia Genética , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Janus Quinase 3/antagonistas & inibidores , Janus Quinases/antagonistas & inibidores , Janus Quinases/fisiologia , Subpopulações de Linfócitos/imunologia , Camundongos , Terapia de Alvo Molecular , Família Multigênica/genética , Neoplasias/genética , Neoplasias/imunologia , Subunidades Proteicas , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais , Pesquisa Médica Translacional , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia
5.
Rheumatology (Oxford) ; 58(Suppl 1): i27-i33, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30806706

RESUMO

Janus kinase inhibition is promising in the treatment of RA, with already two oral drugs marketed. New compounds are under investigation that are more selective for Janus kinase 1 or Janus kinase 3. Phase II results for filgotinib, upadacitinib, peficitinib and decernotinib are reviewed showing almost consistently a fast dose-dependent clinical improvement similar to already approved drugs tofacitinib and baricitinib. I will reflect on the most frequently reported dose-dependent adverse events and laboratory changes. Some are similar for all drugs of this class, some are more specific for a certain drug, but all may influence future treatment effectiveness in daily practice. This implies the need for a critical evaluation of phase III trials, and eventually trials specifically powered for conclusions on the safety profile and registries once these drugs become marketed. These innovative drugs also need head-to-head trials versus biologics or in-class as well as specific strategy studies to determine their optimal future use.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Adamantano/análogos & derivados , Adamantano/uso terapêutico , Azetidinas/uso terapêutico , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Resultado do Tratamento , Triazóis/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico
6.
Rheumatology (Oxford) ; 58(Suppl 1): i17-i26, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30806707

RESUMO

Tofacitinib and baricitinib are the first orally available, small-molecule inhibitors of Janus kinase (JAK) enzymes to be approved for the treatment of RA. Tofacitinib is a selective JAK1, 3 inhibitor with less activity against JAK2 and TYK2 and baricitinib is a selective, oral JAK1, 2 inhibitor with moderate activity against TYK2 and significantly less activity against JAK3. Both drugs have undergone extensive phase III clinical trials in RA and demonstrated rapid improvements in disease activity, function and patient-reported outcomes as well as disease modification. Tofacitinib 5 mg bd, was approved by the Federal Drug Administration in 2012 for the treatment of RA in patients who are intolerant or unresponsive to MTX. An extended release formulation for the treatment of RA was approved by Federal Drug Administration in 2016. In 2017 the European Medicines Agency approved tofacitinib 5 mg bd in combination with MTX and baricitinib 4 mg and 2 mg once daily for the treatment of moderate to severe active RA in adult patients who are intolerant or unresponsive to one or more conventional synthetic DMARDs.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Antirreumáticos/uso terapêutico , Quimioterapia Combinada , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Metotrexato/uso terapêutico , Resultado do Tratamento
7.
J Med Chem ; 62(2): 1054-1066, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30615446

RESUMO

JAK family kinases are important mediators of immune cell signaling and Janus Kinase 3 (JAK3) has long been indicated as a potential target for autoimmune disorders. Intensive efforts to develop highly selective JAK3 inhibitors have been underway for many years. However, because of JAK3's strong binding preference to adenosine 5'-triphosphate (ATP), a number of inhibitors exhibit large gaps between enzymatic and cellular potency, which hampers efforts to dissect the roles of JAK3 in cellular settings. Using a targeted covalent inhibitor approach, we discovered compound 32, which overcame ATP competition (1 mM) in the enzymatic assay, and demonstrated significantly improved inhibitory activity for JAK3-dependent signaling in mouse CTLL-2 and human peripheral blood mononuclear cells. Compound 32 also exhibited high selectivity within the JAK family and good pharmacokinetic properties. Thus, it may serve as a highly valuable tool molecule to study the overlapping roles of JAK family kinases in complex biological settings. Our study also suggested that for covalent kinase inhibitors, especially those targeting kinases with low Km ATP values, the reversible interactions between molecules and proteins should be carefully optimized to improve the overall potency.


Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Administração Oral , Animais , Linhagem Celular , Citocinas/metabolismo , Desenho de Drogas , Meia-Vida , Humanos , Janus Quinase 3/metabolismo , Cinética , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
8.
Drug Res (Stuttg) ; 69(6): 330-336, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30193392

RESUMO

A simple, sensitive and rapid assay method has been developed and validated as per regulatory guideline for the estimation of tofacitinib on mice dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electro spray ionization in the positive-ion mode. The method employs liquid extraction of tofacitinib from DBS disk of mice whole blood followed by chromatographic separation using 5 mM ammonium acetate (pH 6.5):acetonitrile (20:80, v/v) at a flow rate of 0.60 mL/min on an X-Terra Phenyl column with a total run time 2.5 min. The MS/MS ion transitions monitored were m/z 313→149 for tofacitinib and m/z 316→149 for the internal standard (13C3, 15N-tofacitinib). The assay was linear in the range of 0.99-1980 ng/mL. The intra- and inter-day precision was in the range of 1.17-10.3 and 3.37-10.9%, respectively. Stability studies showed that tofacitinib was stable on DBS cards for one month. This novel method has been applied to analyze the DBS samples of tofacitinib obtained from a pharmacokinetic study in mice.


Assuntos
Teste em Amostras de Sangue Seco/métodos , Piperidinas/sangue , Inibidores de Proteínas Quinases/sangue , Pirimidinas/sangue , Pirróis/sangue , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Injeções Intravenosas , Janus Quinase 3/antagonistas & inibidores , Masculino , Camundongos , Modelos Animais , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirróis/administração & dosagem , Pirróis/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
9.
Fitoterapia ; 132: 82-87, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30521857

RESUMO

Two new nucleoside derivatives, named asponguanosines A and B (1 and 2), three new N-acetyldopamine analogues, aspongamides C-E (3-5), one new sesquiterpene, aspongnoid D (6), and three known compounds were isolated from the medicinal insect Aspongopus chinensis. Their structures including absolute configurations were assigned by using spectroscopic methods and ECD and 13C NMR calculations. Biological activities of compounds 3-7 towards human cancer cells, COX-2, ROCK1, and JAK3 were evaluated.


Assuntos
Dopamina/análogos & derivados , Heterópteros/química , Nucleosídeos/química , Animais , Carbono-Carbono Liases/química , Carbono-Carbono Liases/isolamento & purificação , Linhagem Celular Tumoral , China , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/isolamento & purificação , Dopamina/química , Dopamina/isolamento & purificação , Humanos , Janus Quinase 3/antagonistas & inibidores , Estrutura Molecular , Nucleosídeos/isolamento & purificação , Quinases Associadas a rho/antagonistas & inibidores
10.
J Pharm Biomed Anal ; 164: 706-712, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30472589

RESUMO

In this study, the thermodynamic dissociation constant (pKa) values of tofacitinib in acetonitrile-water binary mixtures with of 25%, 30%, 35% and 45% (v/v) have been determined at 25-45 °C range of temperatures with reversed-phase liquid chromatography (RPLC). The chromatographic determination was achieved on a Kinetex Core-Shell EVO C18-Phenomenex (150 mm x 4.6 mm, 5 µm) analytical column. For each case pKa values and retention factors of tofacitinib by taking into account the effect of the activity coefficients in hydro-organic water-acetonitrile binary mixtures have been evaluated and which obtain by SOLVER algorithm of spreadsheet program Excel to fit experimental data to the nonlinear expression derived. From these values, the thermodynamic aqueous pKa value of the drug was calculated by different approaches. Thermodynamic parameters standard Gibbs free energy (ΔG°), standard enthalpy (ΔH°) and standard entropy (ΔS°) derived from dissociation constant measurements at six different temperatures were calculated by from linearity plots of IogKa against 1/T (van't Hoff plot).


Assuntos
Cromatografia de Fase Reversa/métodos , Janus Quinase 3/antagonistas & inibidores , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Pirróis/farmacocinética , Acetonitrilos/química , Cromatografia Líquida de Alta Pressão/métodos , Entropia , Piperidinas/química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirróis/química , Temperatura Ambiente , Água/química
11.
J Med Chem ; 61(23): 10665-10699, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30423248

RESUMO

Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.


Assuntos
Cianamida/química , Cianamida/farmacologia , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Cianamida/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Janus Quinase 3/química , Masculino , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Distribuição Tecidual
12.
Dermatol Ther ; 31(5): e12696, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30207045

RESUMO

Pemphigus is a rare, but life-threatening autoimmune disease with a high rate of morbidity and mortality, if left untreated. After the development of corticosteroid therapy in the 1950s, the death rate for pemphigus has significantly decreased. However, finding more potent therapeutic options for refractory patients has remained a controversial topic. In the recent years, rituximab has increasingly been used for the treatment of refractory pemphigus, but some patients do not well-respond. In addition, there is a paucity of evidence to support the risk of diseases exacerbation after rituximab therapy. In this study, as a JAK1 and JAK3 inhibitor, tofacitinib has been proposed for the treatment of refractory pemphigus patients.


Assuntos
Janus Quinases/antagonistas & inibidores , Pênfigo/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Citocinas/metabolismo , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Pênfigo/imunologia , Transdução de Sinais , Células Th2/imunologia , Células Th2/metabolismo
13.
Bioorg Med Chem ; 26(17): 4774-4786, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30139575

RESUMO

Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1H-pyrazolo[3,4-d]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound 12a, which exhibited potent JAK3 inhibitory activity (IC50 of 6.2 nM) as well as excellent JAK kinase selectivity (>60-fold). In cellular assay, 12a exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50 of 9.4 µM). Further, compound 12a showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors.


Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirimidinas/química , Acrilamida/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Interleucina-2/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Espectrometria de Massas por Ionização por Electrospray , Linfócitos T/efeitos dos fármacos
14.
Comput Biol Chem ; 76: 109-117, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29990790

RESUMO

Janus kinase 1 and 3 are non-receptor protein tyrosine kinases, involved in the regulation of various cytokines implicated in the pathogenesis of autoimmune and inflammatory disease conditions. Thus, they serve as therapeutic targets for the designing of multi-targeted agents for the treatment of inflammatory-mediated pathological conditions. In the present study, diverse inhibitors of JAK1 and JAK3 were considered for the development of ligand-based pharmacophore models, followed by docking analysis to design putative dual inhibitors. The pharmacophore models were generated in PHASE 3.4, and top five models for each target were selected on the basis of survival minus inactive score. The best model for JAK1 (AAADH.25) and JAK3 (ADDRR.142) were selected corresponding to the highest value of Q2test. Both models were employed for the screening of a PHASE database, and subsequently, the retrieved hits were filtered employing molecular docking in JAK1 and JAK3 proteins. The stable interactions between retrieved hits and proteins were confirmed using molecular dynamics simulations. Finally, ADME properties of screened dual inhibitors displaying essential interactions with both proteins were calculated. Thus, the new leads obtained in this way may be prioritized for experimental validation as potential novel therapeutic agents in the treatment of various autoimmune and inflammatory disorders related to JAK1 and JAK3.


Assuntos
Janus Quinase 1/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade
15.
J Med Chem ; 61(12): 5350-5366, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29852068

RESUMO

Janus kinases are major drivers of immune signaling and have been the focus of anti-inflammatory drug discovery for more than a decade. Because of the invariable colocalization of JAK1 and JAK3 at cytokine receptors, the question if selective JAK3 inhibition is sufficient to effectively block downstream signaling has been highly controversial. Recently, we discovered the covalent-reversible JAK3 inhibitor FM-381 (23) featuring high isoform and kinome selectivity. Crystallography revealed that this inhibitor induces an unprecedented binding pocket by interactions of a nitrile substituent with arginine residues in JAK3. Herein, we describe detailed structure-activity relationships necessary for induction of the arginine pocket and the impact of this structural change on potency, isoform selectivity, and efficacy in cellular models. Furthermore, we evaluated the stability of this novel inhibitor class in in vitro metabolic assays and were able to demonstrate an adequate stability of key compound 23 for in vivo use.


Assuntos
Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Trifosfato de Adenosina/metabolismo , Animais , Sítios de Ligação , Células Cultivadas , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos/métodos , Estabilidade de Medicamentos , Humanos , Janus Quinase 3/química , Janus Quinase 3/metabolismo , Medições Luminescentes/métodos , Camundongos , Fosforilação/efeitos dos fármacos , Piridinas/química , Fator de Transcrição STAT5/metabolismo , Linfócitos T/efeitos dos fármacos
16.
Br J Dermatol ; 179(4): 853-862, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29782642

RESUMO

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported. OBJECTIVES: To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis. METHODS: Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75). RESULTS: Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54. CONCLUSIONS: In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Psoríase/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Administração Oral , Adulto , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Feminino , Seguimentos , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/imunologia , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Psoríase/diagnóstico , Psoríase/imunologia , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
17.
Transplantation ; 102(7): 1075-1084, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29620612

RESUMO

BACKGROUND: The progression from acute to chronic antibody-mediated rejection in kidney transplant recipients is usually not prevented by current therapeutic options. Here, we investigated whether the use of tofacitinib (TOFA), a Janus kinase 3 inhibitor, was capable of preventing the progression of allograft dysfunction in a Fisher-to-Lewis rat model of kidney transplantation. METHODS: Rats were treated from the third week after transplantation to allow the development of rejection. Treatment was based on cyclosporin A, rapamycin or TOFA. Renal function was assessed at 1, 4, 8, and 12 weeks after transplantation, whereas rat survival, histological lesions, and infiltrating lymphocytes were analyzed at 12 weeks. RESULTS: Tofacitinib prolonged graft survival, preserved tubular and glomerular structures and reduced humoral damage characterized by C4d deposition. Tofacitinib was able to reduce donor-specific antibodies. In addition, T and natural killer cell graft infiltration was reduced in TOFA-treated rats. Although rapamycin-treated rats also showed prolonged graft survival, glomerular structures were more affected. Moreover, only TOFA treatment reduced the presence of T, B and natural killer cells in splenic parenchyma. CONCLUSIONS: Tofacitinib is able to reduce the immune response generated in a rat model of kidney graft rejection, providing prolonged graft and recipient survival, better graft function, and less histological lesions.


Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Rim/efeitos adversos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Animais , Doença Crônica/prevenção & controle , Complemento C4b/imunologia , Complemento C4b/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Imunossupressores/uso terapêutico , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Rim/imunologia , Rim/patologia , Masculino , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Resultado do Tratamento
18.
Sci Rep ; 8(1): 5273, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29588471

RESUMO

Janus tyrosine kinase 3 (JAK3) is expressed in lymphoid cells and is involved in the signalling of T cell functions. The development of a selective JAK3 inhibitor has been shown to have a potential benefit in the treatment of autoimmune disorders. In this article, we developed the 4-aminopiperidine-based compound RB1, which was highly selective for JAK3 inhibition, with an IC50 of value of 40 nM, but did not inhibit JAK1, JAK2 or tyrosine kinase 2 (TYK2) at concentrations up to 5 µM. Furthermore, RB1 also exhibited favourable selectivity against a panel of representative kinases. In a battery of cytokine-stimulated cell-based assays, this potent inhibitor of JAK3 activity with good selectivity against other kinases could potently inhibit JAK3 activity over the activity of JAK1 or JAK2 (over at least 100-fold). A combination of liquid chromatography-mass spectrometry (LC-MS) experiments validated that RB1 covalently modified the unique cysteine 909 residue in JAK3. In vivo, RB1 exerted significantly improved pathology in the joints of a collagen-induced arthritis mouse model. The reasonable pharmacokinetics properties (F = 72.52%, T1/2 = 14.6 h) and favourable results of toxicology experiments (LD50 > 2 g/kg) suggest that RB1 has the potential to be an efficacious treatment for RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Janus Quinase 3/antagonistas & inibidores , Articulações/efeitos dos fármacos , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Descoberta de Drogas , Feminino , Humanos , Janus Quinase 3/metabolismo , Articulações/metabolismo , Articulações/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley
19.
Leukemia ; 32(5): 1147-1156, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29434279

RESUMO

Aberrant activation of the JAK3-STAT signaling pathway is a characteristic feature of many hematological malignancies. In particular, hyperactivity of this cascade has been observed in natural killer/T-cell lymphoma (NKTL) cases. Although the first-in-class JAK3 inhibitor tofacitinib blocks JAK3 activity in NKTL both in vitro and in vivo, its clinical utilization in cancer therapy has been limited by the pan-JAK inhibition activity. To improve the therapeutic efficacy of JAK3 inhibition in NKTL, we have developed a highly selective and durable JAK3 inhibitor PRN371 that potently inhibits JAK3 activity over the other JAK family members JAK1, JAK2, and TYK2. PRN371 effectively suppresses NKTL cell proliferation and induces apoptosis through abrogation of the JAK3-STAT signaling. Moreover, the activity of PRN371 has a more durable inhibition on JAK3 compared to tofacitinib in vitro, leading to significant tumor growth inhibition in a NKTL xenograft model harboring JAK3 activating mutation. These findings provide a novel therapeutic approach for the treatment of NKTL.


Assuntos
Janus Quinase 3/antagonistas & inibidores , Linfoma de Células T/tratamento farmacológico , Piridonas/uso terapêutico , Pirimidinas/uso terapêutico , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Xenoenxertos/efeitos dos fármacos , Humanos , Janus Quinase 3/metabolismo , Camundongos , Células T Matadoras Naturais/patologia , Piridonas/farmacologia , Pirimidinas/farmacologia
20.
Eur J Pharmacol ; 825: 28-33, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29458040

RESUMO

Imatinib (IMA) is the standard treatment for CML; however, stopping IMA sometimes results in disease relapse, which suggests that leukemic stem cells (LSCs) remain in such patients, even after complete molecular remission has been achieved. Therefore, new strategies will be required to eradicate LSCs. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is part of the BCR-ABL signaling network, and it is activated in CML, especially in LSCs. JAK2 is known to be associated with CML survival, but the role of JAK3 in CML remains unknown. The antitumor effects of IMA and a JAK3 inhibitor, tofacitinib were examined using the MTT assay in K562 and KCL22. To investigate the mechanisms of action of IMA and the JAK inhibitors in CML cells, we examined apoptosis, the cell cycle, and JAK-STAT signaling using flow cytometry, immunofluorescent microscopy, and Western blotting. The pharmacological inhibition of JAK3 by tofacitinib synergistically enhanced the antitumor effects of IMA in CML cells. Furthermore, the administration of IMA plus a JAK inhibitor reduced the expression of stem cells markers, such as ABCG2 and ALDH1A1. Co-blocking JAK3 with IMA and a JAK3 inhibitor might represent a new treatment strategy for eradicating LSCs and preventing CML relapses.


Assuntos
Antineoplásicos/farmacologia , Mesilato de Imatinib/farmacologia , Janus Quinase 3/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos
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