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1.
World J Gastroenterol ; 30(34): 3929-3931, 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39350781

RESUMO

Tofacitinib is an oral small-molecule Janus kinase (JAK) inhibitor that preferentially inhibits JAK1 and JAK3. Its efficacy in inducing and maintaining remission in ulcerative colitis (UC) as well as its safety profile has been demonstrated in multicenter, randomized, double-blind, placebo-controlled trials. Additionally, real-world studies evaluating the effectiveness and adverse effects of tofacitinib have been conducted, affirming its clinical efficacy in moderate-to-severe UC.


Assuntos
Colite Ulcerativa , Piperidinas , Inibidores de Proteínas Quinases , Pirimidinas , Indução de Remissão , Índice de Gravidade de Doença , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/diagnóstico , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Humanos , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Resultado do Tratamento , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Indução de Remissão/métodos , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Pirróis/uso terapêutico , Pirróis/efeitos adversos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 1/antagonistas & inibidores
2.
Bioorg Chem ; 152: 107762, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39222556

RESUMO

The JAK-STAT signalling pathway is considered to be a significant role involved in the regulation of inflammatory diseases and immune responses, which indicate that specific inhibition of JAK-STAT pathway would be a potential key strategy for RA (Rheumatoid arthritis) treatment. Cedrol (CE), found from ginger by our group earlier, has been proven to play an excellent role in ameliorating RA via acting on JAK3. In this study, 27 new (1, 3-28), along with one known (2) derivatives of CE were synthesized by using chloroacetic acid and acryloyl chloride as intermediate ligands. In vitro, the inhibition effect on JAK kinases were performed using HTRF (Homogenous Time-Resolved Fluorescence) detection technology, which is more convenient and stable than traditional methods. The results compared with the secretion of LPS-induced p-JAK3 can better reflect the true kinase-selective effect of the compounds. Compound 22 was identified as a potent inhibitor to reduce the secretion of LPS-induced p-JAK3 with a dose-dependent manner. Given these results, compound 22 could serve as a favourable inhibitor of JAK3 for further research.


Assuntos
Relação Dose-Resposta a Droga , Desenho de Fármacos , Janus Quinase 3 , Inibidores de Proteínas Quinases , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Humanos , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estrutura Molecular , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos
3.
Drug Metab Dispos ; 52(10): 1124-1136, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39111823

RESUMO

Ritlecitinib is an oral once-daily irreversible inhibitor of Janus kinase 3 and tyrosine-protein kinase family being developed for the treatment of moderate-to-severe alopecia areata. This study examined the disposition of ritlecitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite profiles. The results indicated ritlecitinib had a systemic clearance of 43.7 L/h, a steady state volume of distribution of 73.8 L, extent of absorption of 89%, time to maximum plasma concentration of ∼0.5 hours, and absolute oral bioavailability of 64%. An observed long terminal half-life of total radioactivity was primarily attributed to ritlecitinib binding to plasma albumin. Ritlecitinib was the main circulating drug species in plasma (∼30%), with one major pharmacologically inactive cysteine conjugated metabolite (M2) at >10%. Oxidative metabolism (fractional clearance 0.47) and glutathione-related conjugation (fractional clearance 0.24) were the primary routes of elimination for ritlecitinib with the greatest disposition of radioactivity shown in the urine (∼71%). In vitro phenotyping indicated ritlecitinib cytochrome P450 (CYP) fraction of metabolism assignments of 0.29 for CYP3A, 0.09 for CYP2C8, 0.07 for CYP1A2, and 0.02 for CYP2C9. In vitro phenotyping in recombinant human glutathione S-transferases indicated ritlecitinib was turned over by a number of cytosolic and microsomal enzyme isoforms. SIGNIFICANCE STATEMENT: This study provides a detailed understanding of the disposition and metabolism of ritlecitinib, a JAK3 and TEC family kinase inhibitor for alopecia areata in humans, as well as characterization of clearance pathways and pharmacokinetics of ritlecitinib and its metabolites. As an AMS-based ADME study design, we have expanded on reporting the standard ADME endpoints, providing key pharmacokinetic parameters, such as clearance, volume of distribution, and bioavailability, allowing for a more comprehensive understanding of drug disposition.


Assuntos
Inibidores de Proteínas Quinases , Humanos , Masculino , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Adulto , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Administração Oral , Adulto Jovem , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Disponibilidade Biológica , Meia-Vida , Administração Intravenosa
4.
Arch Dermatol Res ; 316(7): 478, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39023568

RESUMO

The efficacy of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on active and stable lesions was evaluated in patients with active non-segmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to placebo or daily ritlecitinib 50 mg (with or without 4-week 100-mg or 200-mg loading dose), 30 mg, or 10 mg for 24 weeks. Active lesions showed greater baseline expression of inflammatory/immune markers IFNG and CCL5, levels of CD103, and T-cell infiltrates than stable lesions. Patients with more active than stable vitiligo lesions showed higher baseline serum levels of CXCL9 and PD-L1, while patients with more stable than active lesions showed higher baseline serum levels of HO-1. At Week 24, ritlecitinib 50 mg significantly stabilized mean percent change from baseline in depigmentation extent in both active lesions and stable lesions vs. placebo-response, with stable lesions showing greater repigmentation. After 24 weeks of treatment, ritlecitinib 50 mg increased expression of melanocyte markers in stable lesions, while Th1/Th2-related and co-stimulatory molecules decreased significantly in both stable and active lesions. Serum from patients with more active than stable lesions showed decreased levels of ICOS and NK cell activation markers. These data, confirmed at transcription/protein levels, indicate that stable lesion repigmentation occurs early with ritlecitinib, while active lesions require stabilization of inflammation first. ClinicalTrials.gov: NCT03715829.


Assuntos
Janus Quinase 3 , Inibidores de Proteínas Quinases , Vitiligo , Humanos , Vitiligo/tratamento farmacológico , Vitiligo/diagnóstico , Vitiligo/imunologia , Masculino , Feminino , Adulto , Janus Quinase 3/antagonistas & inibidores , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Resultado do Tratamento , Quimiocina CXCL9/sangue , Quimiocina CCL5/sangue , Adulto Jovem , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Antígeno B7-H1/sangue , Melanócitos/efeitos dos fármacos , Método Duplo-Cego , Pigmentação da Pele/efeitos dos fármacos , Administração Oral , Interferon gama
5.
Molecules ; 29(11)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38893334

RESUMO

Thiazolin-4-ones and their derivatives represent important heterocyclic scaffolds with various applications in medicinal chemistry. For that reason, the synthesis of two 5-substituted thiazolidin-4-one derivatives was performed. Their structure assignment was conducted by NMR experiments (2D-COSY, 2D-NOESY, 2D-HSQC and 2D-HMBC) and conformational analysis was conducted through Density Functional Theory calculations and 2D-NOESY. Conformational analysis showed that these two molecules adopt exo conformation. Their global minimum structures have two double bonds (C=N, C=C) in Z conformation and the third double (C=N) in E. Our DFT results are in agreement with the 2D-NMR measurements. Furthermore, the reaction isomerization paths were studied via DFT to check the stability of the conformers. Finally, some potential targets were found through the SwissADME platform and docking experiments were performed. Both compounds bind strongly to five macromolecules (triazoloquinazolines, mglur3, Jak3, Danio rerio HDAC6 CD2, acetylcholinesterase) and via SwissADME it was found that these two molecules obey Lipinski's Rule of Five.


Assuntos
Conformação Molecular , Simulação de Acoplamento Molecular , Tiazolidinas , Tiazolidinas/química , Tiazolidinas/síntese química , Isomerismo , Animais , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Peixe-Zebra , Espectroscopia de Ressonância Magnética , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Janus Quinase 3/química , Estrutura Molecular
6.
Transpl Immunol ; 85: 102075, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38936745

RESUMO

BACKGROUND: Despite the significant role of JAK3 in various autoimmune diseases, including graft-versus-host disease (GVHD), there has been a lack of potent and selective JAK3 inhibitors specifically studied for GVHD. In our preclinical investigations, we evaluated a novel JAK3 inhibitor called CS12192, which is already undergoing clinical investigation in autoimmune diseases. METHODS: We evaluated the efficacy of CS12192 in GVHD through mixed lymphocyte reaction (MLR) in both mouse and human cells, as well as allogeneic bone marrow transplantation (BMT) in a murine model. RESULTS: CS12192, starting at a concentration of 0.5 µM, dose-dependently reduced the intracellular positivity for cytokines TNF-α and IFN-γ in CD4+ T cells (p < 0.05 to p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001) during mouse allogeneic MLR assays. This effect was observed for both single and double positivity of the cytokines. Moreover, In MLR assays with three different human donors, CS12192 also demonstrated a dose-dependent reduction in the proportion of IFN-γ positive CD4+ T cells (p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001). Additionally, it suppressed T cell proliferation in the mouse MLR (p < 0.05 to p < 0.0001), but this effect was observed in only one human donor (p < 0.001 to p < 0.0001). Furthermore, the administration of CS12192 at 40 and 80 mg/kg BID significantly improved the survival rate in the BMT model, resulting in cumulative 62-day survival rates of 88.89% (p < 0.01) and 100% (p < 0.001), respectively, compared with prednisolone (p < 0.05). CONCLUSIONS: CS12192 is a novel, potent and selective JAK3 inhibitor demonstrating great potential to mitigate acute GVHD.


Assuntos
Transplante de Medula Óssea , Doença Enxerto-Hospedeiro , Janus Quinase 3 , Animais , Humanos , Camundongos , Doença Aguda , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/tratamento farmacológico , Interferon gama/metabolismo , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/farmacologia , Teste de Cultura Mista de Linfócitos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nitrilas/uso terapêutico , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Transplante Homólogo , Fator de Necrose Tumoral alfa/metabolismo
7.
Gene ; 927: 148719, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-38917875

RESUMO

Renal cell carcinoma (RCC) represents a significant portion of genitourinary cancers, marked by challenging prognosis and high metastasis rates. Immunotherapy has been applied in managing advanced renal cell carcinoma, but the therapeutic outcomes are unsatisfactory. In this study, we order to construct a Janus kinase/signal transduction and activator transcriptional (JAK/STAT)-related signature linked to kidney patient outcomes for better predicting the efficacy to immune checkpoint inhibitors (ICIs) and to provide guidance for effective combination therapy. We screened 25 differentially expressed genes (DEGs) that exhibited high expression in RCC samples and were enriched in the JAK-STAT signaling pathway. Among these genes, 11 key genes were identified and correlated with the expectation of Kidney Clear Cell Carcinoma (KIRC) patients and all these genes was significantly elevated in RCC tumor tissues and cancer cells compared to para-cancer tissues and normal renal cells. Utilizing these 11 genes, we divided RCC patients into high-risk and low-risk groups. We found a clear correlation between the clinicopathologic factors of KIRC patients and the JAK-STAT-related risk score. And the IHC results shown that the JAK3 and STAT4 expression of tumor was significantly higher than normal tissue in RCC patients, the level of JAK3 and STAT4 was positively related to the T stage of RCC patients. In addition, high-risk patients had a poorer prognosis and greater protumor immune cell infiltration, and benefitted less from immunotherapy than did low-risk patients. Furthermore, the JAK-STAT-related risk score can predict disease-free survival (DFS) in RCC patients according to the nomogram, which constructed in combination with other clinical features such as age, TNM-staging and stage. Our study demonstrated the JAK-STAT signaling pathway's important regulatory function in RCC tumor immunity. This insight not only enhances our ability to accurately predict the survival rate of RCC patients, but also underscores a potential therapeutic alternative for RCC, involving the combined targeting of the JAK-STAT pathway and immune checkpoints.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais , Regulação Neoplásica da Expressão Gênica , Imunoterapia , Neoplasias Renais , Transdução de Sinais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Imunoterapia/métodos , Feminino , Masculino , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/metabolismo , Janus Quinase 3/genética , Janus Quinase 3/metabolismo , Janus Quinases/metabolismo , Janus Quinases/genética , Pessoa de Meia-Idade , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Transcriptoma , Perfilação da Expressão Gênica
8.
Immunopharmacol Immunotoxicol ; 46(4): 529-537, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38918174

RESUMO

OBJECTIVE: Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models. METHODS: Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB)-induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly. RESULTS: In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor. CONCLUSION: Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.


Assuntos
Modelos Animais de Doenças , Janus Quinase 1 , Janus Quinase 3 , Proteínas Serina-Treonina Quinases , Sulfonamidas , Animais , Camundongos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Janus Quinase 3/antagonistas & inibidores , Sulfonamidas/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Feminino , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Purinas/farmacologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/imunologia , Azetidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Psoríase/patologia , Psoríase/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Pirazóis
9.
Bioorg Chem ; 149: 107499, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38815476

RESUMO

Janus Kinase 3 (JAK3) is important for the signaling transduction of cytokines in immune cells and is identified as potential target for treatment of rheumatoid arthritis (RA). Recently, we designed and synthesized two JAK3 inhibitors J1b and J1f, which featured with high selectivity but mild bioactivity. Therefore, in present study the structure was optimized to increase the potency. As shown in the results, most of the compounds synthesized showed stronger inhibitory activities against JAK3 in contrast to the lead compounds, among which 9a was the most promising candidate because it had the most potent effect in ameliorating carrageenan-induced inflammation of mice and exhibited low acute in vivo toxicity (MTD > 2 g/kg). Further analysis revealed that 9a was highly selective to JAK3 (IC50 = 0.29 nM) with only minimal effect on other JAK members (>3300-fold) and those kinases bearing a thiol in a position analogous to that of Cys909 in JAK3 (>150-fold). Meanwhile, the selectivity of JAK3 was also confirmed by PBMC stimulation assay, in which 9a irreversibly bound to JAK3 and robustly inhibited the signaling transduction with mild suppression on other JAKs. Moreover, it was showed that 9a could remarkably inhibited the proliferation of lymphocytes in response to concanavalin A and significantly mitigate disease severity in collagen induced arthritis. Therefore, present data indicate that compound 9a is a selective JAK3 inhibitor and could be a promising candidate for clinical treatment of RA.


Assuntos
Artrite Reumatoide , Janus Quinase 3 , Inibidores de Proteínas Quinases , Pirimidinas , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Artrite Reumatoide/tratamento farmacológico , Animais , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Humanos , Relação Estrutura-Atividade , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Estrutura Molecular , Relação Dose-Resposta a Droga , Pirróis/química , Pirróis/farmacologia , Pirróis/síntese química , Carragenina , Masculino , Artrite Experimental/tratamento farmacológico , Artrite Experimental/induzido quimicamente , Antirreumáticos/farmacologia , Antirreumáticos/química , Antirreumáticos/síntese química , Simulação de Acoplamento Molecular
10.
Apoptosis ; 29(9-10): 1738-1756, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38641760

RESUMO

To investigate the protective role of immune response gene 1 (IRG1) and exogenous itaconate in autoimmune hepatitis (AIH) and elucidate the underlying mechanisms. Wild-type and IRG1-/- AIH mouse models were established, and samples of liver tissue and ocular blood were collected from each group of mice to assess the effects of IRG1/itaconate on the expression of pro- and anti-inflammatory cytokines. The levels of liver enzymes and related inflammatory factors were determined using enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR). Liver histomorphology was detected through hematoxylin and eosin staining and then scored for liver injury, and the infiltration levels of tissue-resident memory T (TRM) cells and related molecules in the liver tissue were detected through immunofluorescence staining in vitro. RNA sequencing and gene enrichment analysis were conducted to identify the corresponding molecules and pathways, and lentiviral transfection was used to generate TRM cell lines with IRG1, Jak3, Stat3, and p53 knockdown. Real-time quantitative PCR and western blot were performed to detect the expression levels of relevant mRNAs and proteins in the liver tissue and cells. The percentage of apoptotic cells was determined using flow cytometry. IRG1/itaconate effectively reduced the release of pro-inflammatory cytokines and the pathological damage to liver tissue, thereby maintaining normal liver function. At the same time, IRG1/itaconate inhibited the JAK3/STAT3 signaling pathway, regulated the expression of related downstream proteins, and inhibited the proliferation and promoted the apoptosis of CD69+CD103+CD8+ TRM cells. For the first time, P53 was found to act as a downstream molecule of the JAK3/STAT3 pathway and was regulated by IRG1/itaconate to promote the apoptosis of CD8+ TRM cells. IRG1/itaconate can alleviate concanavalin A-induced autoimmune hepatitis in mice by inhibiting the proliferation and promoting the apoptosis of CD69+CD103+CD8+ TRM cells via the JAK3/STAT3/P53 pathway.


Assuntos
Antígenos de Diferenciação de Linfócitos T , Apoptose , Linfócitos T CD8-Positivos , Proliferação de Células , Hepatite Autoimune , Cadeias alfa de Integrinas , Janus Quinase 3 , Fator de Transcrição STAT3 , Proteína Supressora de Tumor p53 , Animais , Camundongos , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Hepatite Autoimune/genética , Hepatite Autoimune/tratamento farmacológico , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/metabolismo , Janus Quinase 3/genética , Janus Quinase 3/metabolismo , Janus Quinase 3/antagonistas & inibidores , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Fígado/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/imunologia , Células T de Memória/imunologia , Células T de Memória/metabolismo , Células T de Memória/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética
11.
J Transl Med ; 22(1): 370, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637842

RESUMO

JAK-STAT signalling pathway inhibitors have emerged as promising therapeutic agents for the treatment of hair loss. Among different JAK isoforms, JAK3 has become an ideal target for drug discovery because it only regulates a narrow spectrum of γc cytokines. Here, we report the discovery of MJ04, a novel and highly selective 3-pyrimidinylazaindole based JAK3 inhibitor, as a potential hair growth promoter with an IC50 of 2.03 nM. During in vivo efficacy assays, topical application of MJ04 on DHT-challenged AGA and athymic nude mice resulted in early onset of hair regrowth. Furthermore, MJ04 significantly promoted the growth of human hair follicles under ex-vivo conditions. MJ04 exhibited a reasonably good pharmacokinetic profile and demonstrated a favourable safety profile under in vivo and in vitro conditions. Taken together, we report MJ04 as a highly potent and selective JAK3 inhibitor that exhibits overall properties suitable for topical drug development and advancement to human clinical trials.


Assuntos
Desenvolvimento de Medicamentos , Cabelo , Camundongos , Animais , Humanos , Camundongos Nus , Descoberta de Drogas , Janus Quinase 3
12.
J Clin Immunol ; 44(4): 98, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38598033

RESUMO

Biallelic null or hypomorphic variants in JAK3 cause SCID and less frequently Omenn syndrome. We investigated homozygous hypomorphic JAK3 mutations in two patients, and expression and function of a novel JAK3R431P variant in Omenn syndrome. Immunophenotyping of PBMC from the patient with the novel JAK3R431P variant was undertaken, by flow cytometry and Phosflow after stimulation with IL-2, IL-7, and IL-15. JAK3 expression was investigated by Western blotting. We report two patients with homozygous hypomorphic JAK3 variants and clinical features of Omenn syndrome. One patient had a previously described JAK3R775H variant, and the second had a novel JAK3R431P variant. One patient with a novel JAK3R431P variant had normal expression of JAK3 in immortalised EBV-LCL cells but reduced phosphorylation of STAT5 after stimulation with IL-2, IL-7, and IL-15 consistent with impaired kinase activity. These results suggest the JAK3R431P variant to be hypomorphic. Both patients are alive and well after allogeneic haematopoietic stem cell transplantation. They have full donor chimerism, restitution of thymopoiesis and development of appropriate antibody responses following vaccination. We expand the phenotype of hypomorphic JAK3 deficiency and demonstrate the importance of functional testing of novel variants in disease-causing genes.


Assuntos
Janus Quinase 3 , Imunodeficiência Combinada Severa , Humanos , Lactente , Interleucina-15 , Interleucina-2 , Interleucina-7 , Janus Quinase 3/genética , Leucócitos Mononucleares , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia
13.
Clin Exp Rheumatol ; 42(9): 1736-1743, 2024 09.
Artigo em Inglês | MEDLINE | ID: mdl-38530663

RESUMO

OBJECTIVES: To explore the effectiveness of tofacitinib for immunoglobulin G4-related disease (IgG4-RD) and idiopathic retroperitoneal fibrosis (IRF), and investigate the expression of JAKs in the lesion of these diseases. METHODS: Clinical data of patients with IgG4-RD or IRF who were administered with tofacitinib monotherapy were collected. IgG4-RD responder index (IgG4-RD RI) was assessed. The expression of JAK1, JAK2, JAK3, and TYK2 were analysed with immunohistochemistry staining in three salivary glands specimens of IgG4-RD and one retroperitoneal tissue of IRF. RESULTS: Two patients with IRF and two patients with IgG4-RD used tofacitinib monotherapy. Two patients with IRF achieved complete remission with diminished retroperitoneal mass and decreased CRP, as IgG4-RD RI decreased from 6 to 1 in both of them. One with IgG4-RD achieved complete remission with alleviated enlargement of pancreas and IgG4 level decreased from 13.7 g/L to 2.4 g/L, as IgG4-RD RI decreased from 12 to 1. One with IgG4-RD achieved partial response with IgG4 level decreased from 77.1g/L to 25.8g/L as IgG4-RD RI from 18 to 6. JAK1, JAK2, JAK3, and TYK2 expression were detected in biopsy tissues. The staining intensity of the JAK family on the lesion from one IRF patient was similar to those from IgG4-RD patients. CONCLUSIONS: Tofacitinib is a potentially effective treatment for IgG4-RD and IRF and it is reasonable to conduct clinical trial to validate its efficacy. The JAKs were expressed in the inflammatory lesions of IgG4-RD and IRF and they may share a common pathogenesis pathway that is independent of IgG4 production.


Assuntos
Doença Relacionada a Imunoglobulina G4 , Piperidinas , Inibidores de Proteínas Quinases , Pirimidinas , Fibrose Retroperitoneal , TYK2 Quinase , Humanos , Piperidinas/uso terapêutico , Fibrose Retroperitoneal/tratamento farmacológico , Pirimidinas/uso terapêutico , Doença Relacionada a Imunoglobulina G4/tratamento farmacológico , Doença Relacionada a Imunoglobulina G4/diagnóstico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento , Feminino , Janus Quinase 1 , Janus Quinase 2 , Janus Quinase 3 , Idoso , Indução de Remissão , Adulto , Imunoglobulina G , Inibidores de Janus Quinases/uso terapêutico
14.
Int J Mol Sci ; 25(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474223

RESUMO

The Janus kinase (JAK) family is a small group of protein tyrosine kinases that represent a central component of intracellular signaling downstream from a myriad of cytokine receptors. The JAK3 family member performs a particularly important role in facilitating signal transduction for a key set of cytokine receptors that are essential for immune cell development and function. Mutations that impact JAK3 activity have been identified in a number of human diseases, including somatic gain-of-function (GOF) mutations associated with immune cell malignancies and germline loss-of-function (LOF) mutations associated with immunodeficiency. The structure, function and impacts of both GOF and LOF mutations of JAK3 are highly conserved, making animal models highly informative. This review details the biology of JAK3 and the impact of its perturbation in immune cell-related diseases, including relevant animal studies.


Assuntos
Síndromes de Imunodeficiência , Neoplasias , Animais , Humanos , Janus Quinase 3/metabolismo , Transdução de Sinais , Janus Quinases/metabolismo , Receptores de Citocinas/metabolismo , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo
15.
Int Immunopharmacol ; 132: 111931, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38547769

RESUMO

Peficitinib is a selective Janus kinase (JAK3) inhibitor recently developed and approved for the treatment of rheumatoid arthritis in Japan. Glycolysis in macrophages could induce NOD-like receptor (NLR) family and pyrin domain-containing protein 3 (NLRP3) inflammasome activation, thus resulting in pyroptosis and acute lung injury (ALI). The aim of our study was to investigate whether Peficitinib could alleviate lipopolysaccharide (LPS)-induced ALI by inhibiting NLRP3 inflammasome activation. Wild type C57BL/6J mice were intraperitoneally injected with Peficitinib (5 or 10 mg·kg-1·day-1) for 7 consecutive days before LPS injection. The results showed that Peficitinib pretreatment significantly relieved LPS-induced pulmonary edema, inflammation, and apoptosis. NLRP3 inflammasome and glycolysis in murine lung tissues challenged with LPS were also blocked by Peficitinib. Furthermore, we found that the activation of JAK3/signal transducer and activator of transcription 3 (STAT3) was also suppressed by Peficitinib in mice with ALI. However, in Jak3 knockout mice, Peficitinib did not show obvious protective effects after LPS injection. In vitro experiments further showed that Jak3 overexpression completely abolished Peficitinib-elicited inhibitory effects on pyroptosis and glycolysis in LPS-induced RAW264.7 macrophages. Finally, we unveiled that LPS-induced activation of JAK3/STAT3 was mediated by toll-like receptor 4 (TLR4) in RAW264.7 macrophages. Collectively, our study proved that Peficitinib could protect against ALI by blocking JAK3-mediated glycolysis and pyroptosis in macrophages, which may serve as a promising candidate against ALI in the future.


Assuntos
Lesão Pulmonar Aguda , Adamantano/análogos & derivados , Glicólise , Janus Quinase 3 , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Niacinamida , Niacinamida/análogos & derivados , Fator de Transcrição STAT3 , Transdução de Sinais , Animais , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Janus Quinase 3/metabolismo , Janus Quinase 3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Glicólise/efeitos dos fármacos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Masculino , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos Knockout , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Inflamassomos/metabolismo , Piroptose/efeitos dos fármacos , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia
16.
Arch Pharm (Weinheim) ; 357(6): e2300753, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38442328

RESUMO

Selective inhibition of Janus kinase 3 (JAK3) is a promising strategy for the treatment of autoimmune diseases. Based on the discovery of a hydrophobic pocket unutilized between the lead compound RB1 and the JAK3 protein, a series of covalent JAK3 inhibitors were prepared by introducing various aromatic fragments to RB1. Among them, J1b (JAK3 IC50 = 7.2 nM, other JAKs IC50 > 1000 nM) stood out because of its low toxicity (MTD > 2 g/kg) and superior anti-inflammatory activity in Institute of Cancer Research mice. Moreover, the acceptable bioavailability (F% = 31.69%) ensured that J1b displayed excellent immune regulation in collagen-induced arthritis mice, whose joints in the high-dose group were almost recovered to a normal state. Given its clear kinase selectivity (Bmx IC50 = 539.9 nM, other Cys909 kinases IC50 > 1000 nM), J1b was nominated as a highly selective JAK3 covalent inhibitor, which could be used to safely treat arthritis and other autoimmune diseases.


Assuntos
Artrite Experimental , Artrite Reumatoide , Desenho de Fármacos , Janus Quinase 3 , Inibidores de Proteínas Quinases , Animais , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Camundongos , Artrite Experimental/tratamento farmacológico , Artrite Experimental/induzido quimicamente , Artrite Experimental/enzimologia , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Camundongos Endogâmicos DBA , Humanos , Relação Dose-Resposta a Droga , Estrutura Molecular , Masculino , Simulação de Acoplamento Molecular
17.
J Pharmacol Exp Ther ; 389(1): 40-50, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38336380

RESUMO

B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was tested for its ability to alter disease progression in a mouse model of B-ALL. Mb1-CreΔPB mice have deletions in genes encoding PU.1 and Spi-B in B cells and develop B-ALL at 100% incidence. Treatment of Mb1-CreΔPB mice with NAC in drinking water significantly reduced the frequency of CD19+ pre-B-ALL cells infiltrating the thymus at 11 weeks of age. However, treatment with NAC did not reduce leukemia progression or increase survival by a median 16 weeks of age. NAC significantly altered gene expression in leukemias in treated mice. Mice treated with NAC had increased frequencies of activating mutations in genes encoding Janus kinases 1 and 3. In particular, frequencies of Jak3 R653H mutations were increased in mice treated with NAC compared with control drinking water. NAC opposed oxidization of PTEN protein ROS in cultured leukemia cells. These results show that NAC alters leukemia progression in this mouse model, ultimately selecting for leukemias with high Jak3 R653H mutation frequencies. SIGNIFICANCE STATEMENT: In a mouse model of precursor B-cell acute lymphoblastic leukemia associated with high levels of reactive oxygen species, treatment with N-acetylcysteine did not delay disease progression but instead selected for leukemic clones with activating R653H mutations in Janus kinase 3.


Assuntos
Água Potável , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Camundongos , Animais , Pré-Escolar , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Janus Quinases , Taxa de Mutação , Espécies Reativas de Oxigênio/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Mutação , Janus Quinase 3/genética , Janus Quinase 3/metabolismo , Progressão da Doença
18.
Am J Clin Dermatol ; 25(2): 299-314, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38263353

RESUMO

BACKGROUND: The ALLEGRO phase 2a and 2b/3 studies demonstrated that ritlecitinib, an oral JAK3/TEC family kinase inhibitor, is efficacious at doses of ≥ 30 mg in patients aged ≥ 12 years with alopecia areata (AA). OBJECTIVE: The objective of this study was to evaluate the safety of ritlecitinib in an integrated analysis of four studies in AA. METHODS: Two cohorts were analyzed: a placebo-controlled and an all-exposure cohort. Proportions and study size-adjusted incidence rates (IRs) of adverse events (AEs) of interest and laboratory abnormalities are reported. RESULTS: In the placebo-controlled cohort (n = 881; median exposure: 169 days), the proportion of ritlecitinib-treated patients with AEs was 70.2-75.4% across doses versus 69.5% in the placebo group; serious AEs occurred in 0-3.2% versus 1.9% for the placebo. A total of 19 patients permanently discontinued due to AEs (5 while receiving the placebo). In the all-exposure cohort (n = 1294), median ritlecitinib exposure was 624 days [2091.7 total patient-years (PY)]. AEs were reported in 1094 patients (84.5%) and serious AEs in 57 (4.4%); 78 (6.0%) permanently discontinued due to AEs. The most common AEs were headache (17.7%; 11.9/100 PY), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (15.5%; 9.8/100 PY), and nasopharyngitis (12.4%; 8.2/100 PY). There were two deaths (breast cancer and acute respiratory failure/cardiorespiratory arrest). Proportions (IRs) were < 0.1% (0.05/100 PY) for opportunistic infections, 1.5% (0.9/100 PY) for herpes zoster, 0.5% (0.3/100 PY) for malignancies (excluding nonmelanoma skin cancer), and 0.2% (0.1/100 PY) for major adverse cardiovascular events. CONCLUSIONS: Ritlecitinib is well tolerated with an acceptable safety profile up to 24 months in patients aged ≥ 12 years with AA (video abstract and graphical plain language summary available). TRIAL REGISTRIES: ClinicalTrials.gov: NCT02974868 (date of registration: 11/29/2016), NCT04517864 (08/18/2020), NCT03732807 (11/07/2018), and NCT04006457 (07/05/2019).


Assuntos
Alopecia em Áreas , Antineoplásicos , Triptaminas , Humanos , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/epidemiologia , Carbazóis , Janus Quinase 3 , Inibidores de Proteínas Quinases/efeitos adversos , SARS-CoV-2 , Resultado do Tratamento
19.
Mol Biomed ; 5(1): 3, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38172378

RESUMO

The disruptor of telomeric silencing 1-like (DOT1L), a specific histone methyltransferase that catalyzed methylation of histone H3 on lysine 79, was associated with the pathogenesis of many diseases, but its role in peritoneal fibrosis remained unexplored. Here, we examined the role of DOT1L in the expression and activation of protein tyrosine kinases and development of peritoneal fibrosis. We found that a significant rise of DOT1L expression in the fibrotic peritoneum tissues from long-term PD patients and mice. Inhibition of DOT1L significantly attenuated the profibrotic phenotypic differentiation of mesothelial cells and macrophages, and alleviated peritoneal fibrosis. Mechanistically, RNA sequencing and proteomic analysis indicated that DOT1L was mainly involved in the processes of protein tyrosine kinase binding and extracellular matrix structural constituent in the peritoneum. Chromatin immunoprecipitation (ChIP) showed that intranuclear DOT1L guided H3K79me2 to upregulate EGFR in mesothelial cells and JAK3 in macrophages. Immunoprecipitation and immunofluorescence showed that extranuclear DOT1L could interact with EGFR and JAK3, and maintain the activated signaling pathways. In summary, DOT1L promoted the expression and activation of tyrosine kinases (EGFR in mesothelial cells and JAK3 in macrophages), promoting cells differentiate into profibrotic phenotype and thus peritoneal fibrosis. We provide the novel mechanism of dialysis-related peritoneal fibrosis (PF) and the new targets for clinical drug development. DOT1L inhibitor had the PF therapeutic potential.


Assuntos
Histona-Lisina N-Metiltransferase , Fibrose Peritoneal , Proteínas Tirosina Quinases , Animais , Feminino , Humanos , Masculino , Camundongos , Receptores ErbB/metabolismo , Receptores ErbB/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Janus Quinase 3/metabolismo , Janus Quinase 3/genética , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fibrose Peritoneal/patologia , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
20.
J Allergy Clin Immunol ; 153(1): 161-172.e8, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37777018

RESUMO

BACKGROUND: Vitiligo is an autoimmune depigmenting disorder with no effective and safe treatments. Its pathogenesis is not fully elucidated. OBJECTIVE: This substudy of a randomized, double-blind, placebo-controlled phase 2b trial (NCT03715829) evaluated effects of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on skin and blood biomarkers in participants with nonsegmental vitiligo (NSV). METHODS: Sixty-five adults with NSV participated in the substudy and received daily treatment for 24 weeks with placebo (n = 14) or ritlecitinib with or without a 4-week loading dose: 200 (loading dose)/50 mg (n = 13), 100/50 mg (n = 12), 50 mg (n = 11), 30 mg (n = 8), or 10 mg (n = 6). Skin (lesional and nonlesional) biopsy samples were obtained at baseline and at 4 and 24 weeks. Changes from baseline to weeks 4 and 24 in skin and blood molecular and cellular biomarkers were evaluated by RNA sequencing, quantitative real-time PCR, proteomic analysis, and flow cytometry. RESULTS: Ritlecitinib-treated groups showed downregulation of immune biomarkers and upregulation of melanocyte-related markers at weeks 4 and 24 compared to baseline and/or placebo. Significant reductions were seen in CD3+/CD8+ T-cell infiltrates, with significant increases in melanocyte markers (tyrosinase; Melan-A) in NSV lesions in the 50 mg ritlecitinib groups (both P < .05). There was significant, dose-dependent downregulation in T-cell activation, NK, cytotoxic, and regulatory markers in lesional skin (IL-2, IL2-RA, IL-15, CCR7, CD5, CRTAM, NCR1, XCL1, KIR3DL1, FASLG, KLRD; P < .05). TH1 and TH2 markers were also downregulated in lesional skin and blood in a dose-dependent manner (P < .05). Changes in immune biomarkers correlated with clinical response. CONCLUSIONS: Ritlecitinib significantly downregulated proinflammatory biomarkers and increased melanocyte products in skin and blood of participants with NSV, suggesting its potential in treatment. Ritlecitinib-mediated changes positively correlated with clinical response.


Assuntos
Vitiligo , Adulto , Humanos , Vitiligo/tratamento farmacológico , Proteômica , Melanócitos , Pele , Biomarcadores , Janus Quinase 3
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