Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 496
Filtrar
1.
Int J Mol Sci ; 23(4)2022 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-35216314

RESUMO

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling is an attractive therapeutic target for tumor therapy. Herein, forty-eight novel meridianin derivatives were designed and synthesized, and their antitumor activity was evaluated in vitro both for activity optimization and structure-activity relationship (SAR) study. The results indicated that most derivatives exhibited significantly improved antitumor activity, especially for compound 6e. The compound 6e contains an isothiouronium linked by an alkyl chain consisting of six carbon atoms with IC50 ranging from 1.11 to 2.80 µM on various cancer cell lines. Consistently, the 6e dose dependently induced the apoptosis of A549 and DU145 cells, in which STAT3 is constitutively active. Western blotting assays indicated that the phosphorylation levels of JAK1, JAK2 and STAT3 were inhibited by 6e at 5 µM without significant change in the total STAT3 level. Moreover, 6e also suppressed the expression of STAT3 downstream genes, including c-Myc, Cyclin D1 and Bcl-XL at 10 µM. An additional in vivo study revealed that 6e at the dose of 10 mg/kg could potently inhibit the DU145 xenograft tumor without obvious body weight loss. These results clearly indicate that 6e could be a potential antitumor agent by targeting the JAK/STAT3 signaling pathway.


Assuntos
Alcaloides Indólicos , Inibidores de Janus Quinases , Fator de Transcrição STAT3 , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/química , Inibidores de Janus Quinases/farmacologia , Fosforilação , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais , Relação Estrutura-Atividade
2.
J Med Chem ; 65(4): 3151-3172, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35113547

RESUMO

In this study, we described a series of 2,8-diazaspiro[4.5]decan-1-one derivatives as selective TYK2/JAK1 inhibitors. Systematic exploration of the structure-activity relationship through the introduction of spirocyclic scaffolds based on the reported selective TYK2 inhibitor 14l led to the discovery of the superior derivative compound 48. Compound 48 showed excellent potency on TYK2/JAK1 kinases with IC50 values of 6 and 37 nM, respectively, and exhibited more than 23-fold selectivity for JAK2. Compound 48 also demonstrated excellent metabolic stability and more potent anti-inflammatory efficacy than tofacitinib in acute ulcerative colitis models. Moreover, the excellent anti-inflammatory effect of compound 48 was mediated by regulating the expression of related TYK2/JAK1-regulated genes, as well as the formation of Th1, Th2, and Th17 cells. Taken together, these findings suggest that compound 48 is a selective dual TYK2/JAK inhibitor, deserving to be developed as a clinical candidate.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Camundongos , Simulação de Acoplamento Molecular , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
3.
Bioorg Med Chem Lett ; 55: 128451, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34774741

RESUMO

JAK inhibitors have been considered as useful targets for the treatment of related diseases. However, first-generation JAK inhibitors have side effects such as anemia, thrombocytopenia, neutropenia and headaches which have been suggested to result from high JAK2 inhibition. Second-generation JAK inhibitors with more specific JAK isozyme inhibition have been studied to eliminate these adverse effects. In this study, novel 4-(1,5- or 2,5-triazole)-pyrrolopyrimidine derivatives with aromatic moieties were synthesized as JAK1 inhibitors, and an in vitro enzyme assay was used to evaluate the JAK inhibitory effects. Among these JAK1 inhibitors, the compound 23a showed an IC50 level of 72 nM, as well as being selective against other JAKs by 12 times or more: the results of molecular docking studies suggested that the high JAK1 selectivity resulted from a key interaction between the iodine atom of compound 23a and His-885 of hJAK1.


Assuntos
Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Triazóis/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Janus Quinase 1/metabolismo , Inibidores de Janus Quinases/síntese química , Inibidores de Janus Quinases/química , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
4.
Leuk Lymphoma ; 63(1): 189-198, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34521299

RESUMO

ROMEI, a prospective, observational study in patients with myelofibrosis receiving the oral JAK1/2 inhibitor ruxolitinib in real-world practice, assesses treatment adherence based on the 8-item Morisky Medication Adherence Scale (MMAS-8). Here, we present MMAS-8 results at week 24. Overall, 101 of 188 evaluable patients completed the questionnaire at every visit (full completers). Mean (±standard deviation) total MMAS-8 scores remained stable from week 4 to week 24 in the overall population (7.54 ± 0.77 and 7.67 ± 0.70, respectively) and full completers (7.53 ± 0.79 and 7.67 ± 0.73, respectively). Rates of low (MMAS-8 ˂6) or medium (MMAS-8 ≥ 6 to ˂8) adherence were 25-40% and 26-36%, respectively. Fifty-five full completers (54%) reported ≥1 change in adherence category (improvement and/or worsening), most of which were associated with unintentional behavior. The data suggest that one-third of patients receiving ruxolitinib may be undertreated due to non-adherence, potentially undermining disease control, and indicate a need for better interventions addressing noncompliance to oral therapies.


Assuntos
Janus Quinase 1 , Janus Quinase 2 , Mielofibrose Primária , Pirazóis , Pirimidinas , Estudos de Coortes , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Adesão à Medicação , Nitrilas/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Estudos Prospectivos , Psicometria/métodos , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Inquéritos e Questionários
6.
Dev Med Child Neurol ; 64(2): 266-271, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34415581

RESUMO

Janus kinase (JAK) 1 inhibition represents a precision medicine approach in the treatment of Aicardi-Goutières syndrome (AGS), through targeting of type I interferon-mediated cell signalling. Blood interferon mRNAseq has been proposed as a biomarker of disease with utility in therapeutic monitoring. Objective cerebrospinal fluid (CSF) biomarkers tracking treatment efficacy are currently lacking. Here, we report a retrospective case series of 13 patients (median age 6y, range 2y 6mo-17y; five females, eight males) with AGS demonstrating significantly elevated CSF neopterin levels at first sampling (median 200nmol/L, range 45-2024nmol/L), compared to 13 age-matched controls with non-inflammatory neurological conditions (median 23nmol/L, range 5-34nmol/L, p<0.001). Five patients with AGS treated with JAK inhibitors demonstrated a median 81.5% reduction of CSF neopterin (range -36% to -88% change from baseline), compared to eight untreated patients with AGS demonstrating a median 7% reduction in CSF neopterin (range -63% to +117% change) (p=0.047). Our data indicate a biological effect of JAK inhibitors, and the potential role of CSF neopterin as a biomarker of treatment response.


Assuntos
Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Inibidores de Janus Quinases/farmacologia , Neopterina/líquido cefalorraquidiano , Malformações do Sistema Nervoso/líquido cefalorraquidiano , Malformações do Sistema Nervoso/tratamento farmacológico , Adolescente , Biomarcadores/líquido cefalorraquidiano , Criança , Pré-Escolar , Feminino , Humanos , Janus Quinase 1/antagonistas & inibidores , Masculino , Estudos Retrospectivos
7.
Cells ; 10(12)2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34943910

RESUMO

Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30-50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.


Assuntos
Glioblastoma/genética , Síndrome de Li-Fraumeni/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT2/genética , Adolescente , Adulto , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa/genética , Glioblastoma/complicações , Glioblastoma/patologia , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/genética , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Síndrome de Li-Fraumeni/complicações , Síndrome de Li-Fraumeni/patologia , Masculino , Nitrilas/farmacologia , Organoides/metabolismo , Medicina de Precisão , Pirazóis/farmacologia , Pirimidinas/farmacologia , RNA-Seq , Transcriptoma/genética , Adulto Jovem
9.
J Clin Invest ; 131(24)2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34730109

RESUMO

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT using this approach. Mechanistic studies using the JAK1/2 inhibitor baricitinib revealed marked impairment of T and NK cell survival, proliferation, and effector function. NK cells were exquisitely sensitive to JAK1/2 inhibition due to interference with IL-15 signaling. Unlike irradiated mice, ADC-conditioned mice did not develop pathogenic graft-versus-host alloreactivity when challenged with mismatched T cells. Finally, the combination of ADCs and baricitinib balanced graft-versus-host disease and graft-versus-leukemia responses in delayed donor lymphocyte infusion models. Our allo-HSCT conditioning strategy exemplifies the promise of immunotherapy to improve the safety of HSCT for treating hematologic diseases.


Assuntos
Azetidinas/farmacologia , Transplante de Células-Tronco Hematopoéticas , Imunoconjugados/farmacologia , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/farmacologia , Purinas/farmacologia , Pirazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Aloenxertos , Animais , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Leucemia/efeitos dos fármacos , Efeito Enxerto vs Leucemia/genética , Efeito Enxerto vs Leucemia/imunologia , Interleucina-15/genética , Interleucina-15/imunologia , Janus Quinase 1/genética , Janus Quinase 1/imunologia , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Transdução de Sinais/genética , Transdução de Sinais/imunologia
10.
Immunotherapy ; 13(18): 1549-1554, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34645316

RESUMO

Upadacitinib, a selective JAK1 inhibitor, has been evaluated for efficacy and safety in the treatment of psoriatic arthritis (PsA). Relevant literature using the terms 'upadacitinib' and 'PsA' were identified via PubMed and Google Scholar. Efficacy of upadacitinib in the treatment of PsA versus placebo was demonstrated in the SELECT-PsA I and II trials. SELECT-PsA1 also showed upadacitinib was noninferior to adalimumab in the treatment of PsA. The most common adverse events in patients treated with upadacitinib were infections, malignancies and thromboembolic events. Upadacitinib is an effective medication that can be used in the treatment of active PsA. Despite its proven efficacy and safety, upadacitinib does not yet have long-term safety data.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Ensaios Clínicos como Assunto , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos
11.
Cancer Lett ; 523: 182-194, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34627950

RESUMO

Rab1A overexpression has been observed in several cancer types, however, its significance and the underlying mechanisms in non-small cell lung cancer (NSCLC) remain largely unexplored. This study demonstrated that Rab1A overexpression in NSCLC was significantly correlated to short survival and metastasis. Rab1A overexpression promoted cancer cell migration, invasion, and metastasis both in vitro and in vivo, by activating JAK1/STAT6 signaling through stabilizing IL-4Rα protein. Strikingly, high Rab1A level was associated with sensitivity to JAK1 inhibitor, and Rab1A overexpression rendered cancer cells vulnerable to JAK1-targeted agents. JAK1 inhibitor, Itacitinib adipate, dramatically inhibited high Rab1A NSCLC metastasis, in both cell line and patient derived xenograft models. Collectively, these findings demonstrated that Rab1A plays a critical role in the aggressive properties of NSCLC, revealing a unique mechanism by which it promotes metastasis. In addition, we found that Rab1A is a determinant of JAK1 inhibitor sensitivity, which could be explored for improving JAK1-targeted cancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Interleucina-4/fisiologia , Fator de Transcrição STAT6/fisiologia , Proteínas rab1 de Ligação ao GTP/fisiologia , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular , Humanos , Janus Quinase 1/fisiologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Metástase Neoplásica , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Front Immunol ; 12: 720697, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531866

RESUMO

HIV eradication is hindered by the existence of latent HIV reservoirs in CD4+ T cells. Therapeutic strategies targeting latent cells are required to achieve a functional cure, however the study of latently infected cells from HIV infected persons is extremely challenging due to the lack of biomarkers that uniquely characterize them. In this study, the dual reporter virus HIVGKO was used to investigate latency establishment and maintenance in lymphoid-derived CD4+ T cells. Single cell technologies to evaluate protein expression, host gene expression, and HIV transcript expression were integrated to identify and analyze latently infected cells. FDA-approved, JAK1/2 inhibitors were tested in this system as a potential therapeutic strategy to target the latent reservoir. Latent and productively infected tonsillar CD4+ T cells displayed similar activation profiles as measured by expression of CD69, CD25, and HLADR, however latent cells showed higher CXCR5 expression 3 days post-infection. Single cell analysis revealed a small set of genes, including HIST1-related genes and the inflammatory cytokine, IL32, that were upregulated in latent compared to uninfected and productively infected cells suggesting a role for these molecular pathways in persistent HIV infection. In vitro treatment of HIV-infected CD4+ T cells with physiological concentrations of JAK1/2 inhibitors, ruxolitinib and baricitinib, used in clinical settings to target inflammation, reduced latent and productive infection events when added 24 hr after infection and blocked HIV reactivation from latent cells. Our methods using an established model of HIV latency and lymphoid-derived cells shed light on the biology of latency in a crucial anatomical site for HIV persistence and provides key insights about repurposing baricitinib or ruxolitinib to target the HIV reservoir.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Inibidores de Janus Quinases/farmacologia , Latência Viral/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Perfilação da Expressão Gênica , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Humanos , Imunofenotipagem , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Ativação Linfocitária/imunologia , Tonsila Palatina , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Transcriptoma , Ativação Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
13.
Front Immunol ; 12: 704526, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497607

RESUMO

Objective: Baricitinib, a selective inhibitor for janus kinase (JAK) 1 and JAK2, is approved for use in rheumatoid arthritis. Systemic lupus erythematosus (SLE) is recently regarded as a potential candidate targeted by JAK inhibitors because of the relationship between its pathogenesis and JAK/signal transducer and activator of transcription (STAT) pathway-mediated cytokines such as type I interferons. The objective of this study was to determine whether baricitinib could effectively ameliorate SLE using a murine model. Methods: To investigate effects of baricitinib on various autoimmune features, especially renal involvements in SLE, eight-week-old MRL/Mp-Faslpr (MRL/lpr) mice were used as a lupus-prone animal model and treated with baricitinib for eight weeks. Immortalized podocytes and primary podocytes and B cells isolated from C57BL/6 mice were used to determine the in vitro efficacy of baricitinib. Results: Baricitinib remarkably suppressed lupus-like phenotypes of MRL/lpr mice, such as splenomegaly, lymphadenopathy, proteinuria, and systemic autoimmunity including circulating autoantibodies and pro-inflammatory cytokines. It also modulated immune cell populations and effectively ameliorated renal inflammation, leading to the recovery of the expression of structural proteins in podocytes. According to in vitro experiments, baricitinib treatment could mitigate B cell differentiation and restore disrupted cytoskeletal structures of podocytes under inflammatory stimulation by blocking the JAK/STAT pathway. Conclusions: The present study demonstrated that baricitinib could effectively attenuate autoimmune features including renal inflammation of lupus-prone mice by suppressing aberrant B cell activation and podocyte abnormalities. Thus, baricitinib as a selective JAK inhibitor could be a promising therapeutic candidate in the treatment of SLE.


Assuntos
Azetidinas/farmacologia , Lúpus Eritematoso Sistêmico , Podócitos , Purinas/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/imunologia , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Podócitos/imunologia , Podócitos/patologia , Transdução de Sinais/efeitos dos fármacos
14.
Dermatol Online J ; 27(7)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34391330

RESUMO

Dermatitis herpetiformis (DH) is a rare autoimmune blistering disorder in which patients with celiac disease, a gluten-sensitive enteropathy, present with a severely pruritic papulovesicular eruption over extensor surfaces such as the knees, elbows, lower back, buttocks, and neck. Patients are instructed to adhere to a gluten-free diet for purposes of improving their skin disease and gluten-sensitive enteropathy; this is the only treatment that lowers risk of enteropathy-associated T cell lymphoma. Patients who adhere to a strict gluten-free diet often have remission of their skin disease over months to years. Dapsone is a rapid and extremely effective first-line treatment option and often used while transitioning to a gluten-free diet. Aside from gluten-free diet and dapsone, second-line treatment options include sulfapyridine, sulfasalazine, and colchicine. Some patients have difficulty adhering to a gluten-free diet or develop intolerable side effects to systemic therapies. Furthermore, there is limited data on the use of the second-line treatments. Recent studies have shed light on the role of JAK-STAT-dependent pathways in the pathogenesis of dermatitis herpetiformis. We present a patient treated with tofacitinib, 5mg twice daily, an oral JAK1/3 inhibitor, who demonstrated clinical improvement of DH and control of new lesion development.


Assuntos
Doença Celíaca/complicações , Dermatite Herpetiforme/tratamento farmacológico , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Doença Celíaca/dietoterapia , Dapsona/uso terapêutico , Dermatite Herpetiforme/dietoterapia , Dermatite Herpetiforme/etiologia , Dermatite Herpetiforme/patologia , Dieta Livre de Glúten , Esquema de Medicação , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Masculino , Cooperação do Paciente , Indução de Remissão/métodos , Resultado do Tratamento
15.
Am J Clin Dermatol ; 22(6): 877-889, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34374027

RESUMO

BACKGROUND: Atopic dermatitis is a chronic, inflammatory condition causing a substantial burden to patients and caregivers. SHR0302 is an oral, highly selective, Janus kinase 1 inhibitor under investigation for inflammatory skin diseases. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of SHR0302 in Chinese patients with moderate to severe atopic dermatitis. DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, multicenter, phase II trial was conducted in China between October 2019 and August 2020. PARTICIPANTS: Patients (n = 105) aged 18-75 years with moderate to severe dermatitis and nonresponsive or intolerant to topical or conventional systemic treatments were included. INTERVENTIONS: Patients were randomly assigned in a ratio of 1:1:1 to receive SHR0302 4 mg once daily, SHR0302 8 mg once daily, or placebo for 12 weeks. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the proportion of patients achieving Investigator's Global Assessment (IGA) response (IGA of 0 [clear] or 1 [almost clear] with improvement of ≥2 grades) at week 12. Secondary efficacy assessments included Eczema Area and Severity Index (EASI) and pruritus Numerical Rating Scale (NRS) scores. RESULTS: At week 12, IGA response was achieved in nine patients (25.7%; 90% confidence interval [CI] 13.6-37.9%; p = 0.022) in the SHR0302 4 mg group, 19 patients (54.3%; 90% CI 40.4-68.1%; p < 0.001) in the SHR0302 8 mg group, and two patients (5.7%; 90% CI 0.0-12.2%) in the placebo group. EASI75 was achieved in 51.4% (p = 0.013), 74.3% (p < 0.001), and 22.9% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively, while an NRS ≥3-point improvement occurred in 65.7% (p < 0.001), 74.3% (p < 0.001), and 22.9% of patients, respectively. Treatment-emergent adverse events were reported in 60.0%, 68.6%, and 51.4% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively. The adverse events were mild in most cases. Three serious adverse events were reported, all being worsening of atopic dermatitis. No serious infection was reported. CONCLUSIONS AND RELEVANCE: Oral SHR0302 was effective and well tolerated in Chinese adult patients with moderate to severe atopic dermatitis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04162899; URL: https://clinicaltrials.gov/ . Date first registered: 14 November 2019.


Assuntos
Dermatite Atópica/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/administração & dosagem , Ácidos Sulfúricos/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Dermatite Atópica/diagnóstico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Inibidores de Janus Quinases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Ácidos Sulfúricos/efeitos adversos , Resultado do Tratamento , Adulto Jovem
16.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299092

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare multisystem premature aging disorder that leads to early death (mean age of 14.7 years) due to myocardial infarction or stroke. Most cases have a de novo point mutation at position G608G within exon 11 of the LMNA gene. This mutation leads to the production of a permanently farnesylated truncated prelamin A protein called "progerin" that is toxic to the cells. Recently, farnesyltransferase inhibitor (FTI) lonafarnib has been approved by the FDA for the treatment of patients with HGPS. While lonafarnib treatment irrefutably ameliorates HGPS disease, it is however not a cure. FTI has been shown to cause several cellular side effects, including genomic instability as well as binucleated and donut-shaped nuclei. We report that, in addition to these cellular stresses, FTI caused an increased frequency of cytosolic DNA fragment formation. These extranuclear DNA fragments colocalized with cGAs and activated the cGAS-STING-STAT1 signaling axis, upregulating the expression of proinflammatory cytokines in FTI-treated human HGPS fibroblasts. Treatment with lonafarnib and baricitinib, a JAK-STAT inhibitor, not only prevented the activation of the cGAS STING-STAT1 pathway, but also improved the overall HGPS cellular homeostasis. These ameliorations included progerin levels, nuclear shape, proteostasis, cellular ATP, proliferation, and the reduction of cellular inflammation and senescence. Thus, we suggest that combining lonafarnib with baricitinib might provide an opportunity to reduce FTI cellular toxicity and ameliorate HGPS symptoms further than lonafarnib alone.


Assuntos
Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/farmacologia , Piperidinas/efeitos adversos , Progéria/tratamento farmacológico , Purinas/farmacologia , Pirazóis/farmacologia , Piridinas/efeitos adversos , Fator de Transcrição STAT1/antagonistas & inibidores , Sulfonamidas/farmacologia , Adolescente , Células Cultivadas , Pré-Escolar , Farnesiltranstransferase/efeitos adversos , Feminino , Humanos , Masculino , Progéria/induzido quimicamente , Progéria/patologia
17.
Biochem Pharmacol ; 192: 114690, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34274356

RESUMO

BACKGROUND: Eosinophilic asthma is increasingly recognized as one of the most severe and difficult-to-treat asthma subtypes. The JAK/STAT pathway is the principal signaling mechanism for a variety of cytokines and growth factors involved in asthma. However, the direct effect of JAK inhibitors on eosinophil effector function has not been addressed thus far. OBJECTIVE: Here we compared the effects of the JAK1/2 inhibitor baricitinib and the JAK3 inhibitor tofacitinib on eosinophil effector function in vitro and in vivo. METHODS: Differentiation of murine bone marrow-derived eosinophils. Migratory responsiveness, respiratory burst, phagocytosis and apoptosis of human peripheral blood eosinophils were assessed in vitro. In vivo effects were investigated in a mouse model of acute house dust mite-induced airway inflammation in BALB/c mice. RESULTS: Baricitinib more potently induced apoptosis and inhibited eosinophil chemotaxis and respiratory burst, while baricitinib and tofacitinib similarly affected eosinophil differentiation and phagocytosis. Of the JAK inhibitors, oral application of baricitinib more potently prevented lung eosinophilia in mice following allergen challenge. However, both JAK inhibitors neither affected airway resistance nor compliance. CONCLUSION: Our data suggest that the JAK1/2 inhibitor baricitinib is even more potent than the JAK3 inhibitor tofacitinib in suppressing eosinophil effector function. Thus, targeting the JAK1/2 pathway represents a promising therapeutic strategy for eosinophilic inflammation as observed in severe eosinophilic asthma.


Assuntos
Azetidinas/uso terapêutico , Eosinofilia/tratamento farmacológico , Eosinófilos/efeitos dos fármacos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Animais , Azetidinas/farmacologia , Células Cultivadas , Eosinofilia/induzido quimicamente , Eosinofilia/imunologia , Eosinófilos/fisiologia , Feminino , Humanos , Janus Quinase 1/imunologia , Janus Quinase 2/imunologia , Inibidores de Janus Quinases/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Purinas/farmacologia , Pirazóis/farmacologia , Pyroglyphidae/imunologia , Sulfonamidas/farmacologia , Adulto Jovem
18.
Eur J Haematol ; 107(5): 517-528, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34260760

RESUMO

Allogeneic hematopoeitic cell transplantation (allo-HCT) is the only curative treatment for myelofibrosis (MF). We evaluate the impact of various factors on survival outcomes post-transplant in MF. Data of 89 consecutive MF patients (primary 47%) who underwent allo-HCT between 2005 and 2018 was evaluated. Fifty-four percent patients had received JAK1/2 inhibitors (JAKi) pre-HCT. The median CD34 count was 7.1x106 cells/kg. Graft failure was seen in 10% of the patients. Grade 3-4 acute GVHD (aGVHD) and moderate/severe chronic graft versus host disease (cGVHD) occurred in 24% and 40% patients, respectively. Two-year overall survival (OS) and relapse free survival (RFS) were 51% and 43%, respectively. Cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) at 2 years were 11% and 46%, respectively. Higher CD34 cell dose (≤5 × 106 cells/kg vs 5-9 or ≥9 × 106  cells/kg) and lower pre-HCT ferritin (

Assuntos
Antígenos CD34/imunologia , Transplante de Células-Tronco Hematopoéticas , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Mielofibrose Primária/terapia , Inibidores de Proteínas Quinases/farmacologia , Adulto , Idoso , Relação Dose-Resposta Imunológica , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento
20.
J Cell Mol Med ; 25(17): 8187-8200, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34322995

RESUMO

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)-negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.


Assuntos
Azetidinas/farmacologia , Docetaxel/farmacologia , Janus Quinase 1/antagonistas & inibidores , Nitrilas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Purinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...