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1.
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
2.
Life Sci ; 279: 119696, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34102191

RESUMO

AIMS: Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) signaling plays a critical role in the progression of breast cancer. However, a small part of tumor cells survived from the killing effect of JAK2 inhibitor. We aimed to find out the mechanism of drug resistance in breast cancer cells and develop new therapeutic strategies. MATERIALS AND METHODS: The anti-tumor effect of TG101209 in breast cancer cells was confirmed by cell counting kit 8 and flow cytometry. Western blotting was used to determine the up-regulation of zinc finger SWIM-type containing 4 (ZSWIM4) induced by TG101209. In vitro and in vivo experiments were performed to evaluate the role of ZSWIM4 in the resistance of breast cancer cells to TG101209. Through the determination and analysis of 50% inhibiting concentration (IC50) curves, the effect of combination therapy was confirmed. KEY FINDINGS: Our data indicate that the elevated expression of ZSWIM4 contributes to JAK2 inhibition resistance, as knockdown of ZSWIM4 significantly enhances the sensitivity of breast cancer cells to TG101209 and over-expression of this gene mitigates the killing effect. Furthermore, the expression of vitamin D receptor (VDR) and utilization of 1α,25-(OH)2VD3 is decreased in ZSWIM4-knockdown breast cancer cells. VDR-silencing or GW0742-mediated blockade of VDR activity can partially reverse the JAK2 inhibition resistance. SIGNIFICANCE: Our data implicated that ZSWIM4 might be an inducible resistance gene of JAK2 inhibition in breast cancer cells. The combination of JAK2 inhibitor and VDR inhibitor may achieve better coordinated therapeutic effect in breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Janus Quinase 2/antagonistas & inibidores , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Hamostaseologie ; 41(3): 197-205, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34192778

RESUMO

Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of JAK2 signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to JAK2 mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in JAK2, CALR, or MPL in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While JAK2 inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel JAK2 inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.


Assuntos
Células-Tronco Hematopoéticas/patologia , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/terapia , Cromossomo Filadélfia/efeitos dos fármacos , Idoso , Aloenxertos/normas , Calreticulina/genética , Terapia Combinada/métodos , Análise Mutacional de DNA/métodos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Inibidores de Janus Quinases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/fisiopatologia , Nitrilas/uso terapêutico , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Policitemia Vera/patologia , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Trombopoetina/genética , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia
4.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068690

RESUMO

Genetic studies in the past decade have improved our understanding of the molecular basis of the BCR-ABL1-negative myeloproliferative neoplasm (MPN) polycythaemia vera (PV). Such breakthroughs include the discovery of the JAK2V617F driver mutation in approximately 95% of patients with PV, as well as some very rare cases of familial hereditary MPN caused by inherited germline mutations. Patients with PV often progress to fibrosis or acute myeloid leukaemia, both associated with very poor clinical outcome. Moreover, thrombosis and major bleeding are the principal causes of morbidity and mortality. As a result of increasingly available and economical next-generation sequencing technologies, mutational studies have revealed the prognostic relevance of a few somatic mutations in terms of thrombotic risk and risk of transformation, helping to improve the risk stratification of patients with PV. Finally, knowledge of the molecular basis of PV has helped identify targets for directed therapy. The constitutive activation of the tyrosine kinase JAK2 is targeted by ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor for PV patients who are resistant or intolerant to cytoreductive treatment with hydroxyurea. Other molecular mechanisms have also been revealed, and numerous agents are in various stages of development. Here, we will provide an update of the recent published literature on how molecular testing can improve the diagnosis and prognosis of patients with PV and present recent advances that may have prognostic value in the near future.


Assuntos
Janus Quinase 2/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Policitemia Vera/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Humanos , Janus Quinase 2/antagonistas & inibidores , Mutação/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Policitemia Vera/patologia , Prognóstico , Trombose/tratamento farmacológico , Trombose/genética , Trombose/patologia
5.
Cancer Chemother Pharmacol ; 88(3): 369-377, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34019108

RESUMO

PURPOSE: Fedratinib is an oral and selective Janus kinase 2 inhibitor that is indicated for treatment of adults with intermediate-2 or high-risk primary or secondary myelofibrosis. Fedratinib is metabolized by cytochrome P450s (CYPs), primarily CYP3A4. The objective of this study was to determine the effects of the strong CYP3A4 inducer rifampin and moderate CYP3A4 inducer efavirenz on the pharmacokinetics of single doses of fedratinib. METHODS: This Phase 1, open-label, two-part study (Part 1 for rifampin and Part 2 for efavirenz) was conducted in healthy adult men and women. A single dose of fedratinib (500 mg) was administered on Day 1. Participants received rifampin 600 mg daily or efavirenz 600 mg daily on Days 9-18. On Day 17, a single dose of fedratinib (500 mg) was coadministered with rifampin or efavirenz. Plasma fedratinib concentrations were measured using validated liquid chromatography-tandem mass spectrometry. RESULTS: Maximum observed plasma fedratinib concentrations were lowered by approximately 70% and 30% during coadministration with rifampin or efavirenz, respectively, compared with fedratinib alone. Geometric means of fedratinib area under the plasma concentration-time curve from 0 to infinity were decreased by 81% (90% confidence interval [CI], 77-83%) and 47% (90% CI, 40-53%) during coadministration with rifampin or efavirenz, respectively. Fedratinib was generally well tolerated when administered alone or in combination with rifampin or efavirenz. CONCLUSION: Significant reductions in fedratinib exposure were observed in the presence of strong or moderate CYP3A4 inducers. These results suggest that agents that are strong or moderate inducers of CYP3A4 should be avoided when coadministered with fedratinib. TRIAL REGISTRATION NUMBER: NCT03983239 (Registration date: June 12, 2019).


Assuntos
Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Pirrolidinas/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Alcinos/farmacologia , Área Sob a Curva , Benzoxazinas/farmacologia , Cromatografia Líquida , Ciclopropanos/farmacologia , Interações Medicamentosas , Feminino , Humanos , Janus Quinase 2/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirrolidinas/efeitos adversos , Rifampina/farmacologia , Sulfonamidas/efeitos adversos , Espectrometria de Massas em Tandem , Adulto Jovem
6.
Drug Des Devel Ther ; 15: 1705-1716, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935493

RESUMO

Objective: Flavopereirine has been identified to be a potential anti-cancer agent in several types of human cancer. This study aimed to investigate the anti-cancer activity of flavopereirine in oral cancer. Methods: The effect of flavopereirine on cell viability of human oral cancer cell lines (BcaCD885 and Tca8113) was evaluated by MTT assay and colony formation assay. Cell apoptosis and cell cycle distribution were detected by flow cytometry. Cell invasion and migration were evaluated by Transwell assay. The expression of LASP1, JAK2, p-JAK2, STST3, p-STST3, STST5 and p-STST5 was evaluated by qRT-PCR and Western blot. In addition, the xenograft mouse model was constructed to determine the anti-cancer role of flavopereirine in vivo. Results: Flavopereirine significantly inhibited cell proliferation, invasion, migration and EMT process of BcaCD885 and Tca8113 cells, while promoted cell apoptosis in vitro. Flavopereirine markedly decreased the expression levels of p-JAK2, p-STST3 and p-STST5, while increased the expression levels of LASP1. In addition, downregulation of LASP1 significantly increased the expression levels of p-JAK2, p-STAT3 and p-STAT5 compared with si-NC in BcaCD885 cells. Moreover, flavopereirine was found to decrease tumor weight and volume of xenograft tumors in vivo. Conclusion: Flavopereirine inhibited the progression of oral cancer through inactivating the JAK/STAT signaling pathway by upregulating LASP1, suggesting that flavopereirine might be a potential anti-cancer agent for oral cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Antineoplásicos/farmacologia , Carbolinas/farmacologia , Proteínas do Citoesqueleto/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Proteínas com Domínio LIM/antagonistas & inibidores , Neoplasias Bucais/tratamento farmacológico , Fatores de Transcrição STAT/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Janus Quinase 2/metabolismo , Proteínas com Domínio LIM/metabolismo , Estrutura Molecular , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Int Urol Nephrol ; 53(6): 1247-1254, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33942213

RESUMO

AIM: High glucose (HG) induces the production of transforming growth factor (TGF)-ß and reactive oxygen species, which further activates JAK/STAT signaling and promotes the synthesis of matrix proteins, contributes to the pathophysiological processes of diabetic nephropathy. This study aims to investigate the protection role of vitamin D (VD) in the kidney in high glucose condition. METHODS: Rat glomerular mesangial cells were cultured in high glucose medium, with or without VD or VD receptor (VDR) siRNAs treatment. The levels of TGF-ß and fibronectin were detected by qRT-PCR, immunoblotting and enzyme-linked immunosorbent assay (ELISA). The levels of phosphorylated JAK2, STAT1 and STAT3, and JAK/STAT signaling downstream genes were examined by immunoblotting and qRT-PCR. RESULTS: In rat glomerular mesangial cells, VD treatment can repress the tyrosine phosphorylation of JAK2, STAT1 and STAT3. VD inhibited TGF-ß and fibronectin expression which was rescued by vitamin d receptor (VDR) siRNA and STATs inhibitor perficitinib. The JAK/STAT signaling downstream protein coding genes including SOCS1, SOCS3 and type IV collagen were repressed by VD. Meanwhile, the expression of non-coding RNAs such as miR-181a, miR-181b, was repressed by VD, and the expression of miR-34a and Let-7b was upregulated by VD. CONCLUSION: Vitamin D (VD) treatment inhibits the function of HG on fibronectin production through regulating JAK/STAT pathway. These results provide direct evidences that VD protects glomerular mesangial cells from high glucose-induced injury through repressing JAK/STAT signaling, which has the potential for clinical DN treatment.


Assuntos
Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/fisiologia , Células Mesangiais/efeitos dos fármacos , Fator de Transcrição STAT1/antagonistas & inibidores , Fator de Transcrição STAT1/fisiologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/efeitos dos fármacos , Vitamina D/farmacologia , Vitaminas/farmacologia , Animais , Células Cultivadas , Glucose/metabolismo , Masculino , Células Mesangiais/fisiologia , Ratos , Ratos Sprague-Dawley
8.
Cytokine Growth Factor Rev ; 60: 28-45, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33992887

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits an interferon (IFN) deficiency state, which aggravates the type I interferon deficiency and slow IFN responses, which associate with e.g. aging and obesity. Additionally, SARS-CoV-2 may also elicit a cytokine storm, which accounts for disease progression and ultimately the urgent need of ventilator support. Based upon several reports, it has been argued that early treatment with IFN-alpha2 or IFN-beta, preferentially in the early disease stage, may prohibit disease progression. Similarly, preliminary studies have shown that JAK1/2 inhibitor treatment with ruxolitinib or baricitinib may decrease mortality by dampening the deadly cytokine storm, which - in addition to the virus itself - also contributes to multi-organ thrombosis and multi-organ failure. Herein, we describe the rationale for treatment with IFNs (alpha2 or beta) and ruxolitinib emphasizing the urgent need to explore these agents in the treatment of SARS-CoV-2 - both as monotherapies and in combination. In this context, we take advantage of several safety and efficacy studies in patients with the chronic myeloproliferative blood cancers (essential thrombocythemia, polycythemia vera and myelofibrosis) (MPNs), in whom IFN-alpha2 and ruxolitinib have been used successfully for the last 10 (ruxolitinib) to 30 years (IFN) as monotherapies and most recently in combination as well. In the context of these agents being highly immunomodulating (IFN boosting immune cells and JAK1/2 inhibitors being highly immunosuppressive and anti-inflammatory), we also discuss if statins and hydroxyurea, both agents possessing anti-inflammatory, antithrombotic and antiviral potentials, might be inexpensive agents to be repurposed in the treatment of SARS-CoV-2.


Assuntos
COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Interferons/deficiência , Interferons/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , SARS-CoV-2/patogenicidade , Animais , COVID-19/imunologia , COVID-19/patologia , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Humanos , SARS-CoV-2/imunologia
9.
Phytomedicine ; 87: 153552, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33994251

RESUMO

BACKGROUND: The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. PURPOSE: The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. METHODS: The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. RESULTS: Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (α-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-ß (TGF-ß) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. CONCLUSION: Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-ß signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy.


Assuntos
Flavonóis/farmacologia , Hiperuricemia/tratamento farmacológico , Interleucina-6/metabolismo , Nefropatias/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo , Administração Oral , Animais , Fibrose , Flavonóis/administração & dosagem , Flavonóis/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperuricemia/patologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/sangue , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/genética , Ácido Úrico/sangue , Ácido Úrico/urina
10.
Eur J Med Chem ; 218: 113394, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33813153

RESUMO

Herein, we describe the design, synthesis, and structure-activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold, >30-fold and >30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed, at a dose of 20 mg/kg compound 6k, pSTAT3 and pSTAT5 expression was reduced to levels comparable to those of control animals untreated with GM-CSF. Additionally, 6k showed a relatively good bioavailability (F = 38%), a suitable half-life time (T1/2 = 1.9 h), a satisfactory metabolic stability, suggesting that 6k might be a promising inhibitor of JAK2 for further development research for the treatment of MPNs.


Assuntos
Descoberta de Drogas , Imidazóis/farmacologia , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Janus Quinase 2/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Pirróis/síntese química , Pirróis/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
11.
Exp Hematol ; 98: 36-46.e2, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33811972

RESUMO

The objective of this study was to examine the therapeutic effect of ruxolitinib, an orally administered selective Janus kinase (JAK) 1/2 inhibitor, on chronic graft-versus-host disease (cGVHD) using a murine model of sclerodermatous GVHD (scl-GVHD). Compared with scl-GVHD controls, ruxolitinib-treated recipients had scl-GVHD of significantly attenuated clinical and pathological severity in the skin and decreased frequencies of effector cells, CD4+ T cells, and CD11b+ macrophage/monocytes. Regulatory CD4+ Foxp3+ T cells were expanded whereas interferon-γ (IFN-γ)-producing CD4+ T cells were significantly decreased in ruxolitinib-treated recipients. Ruxolitinib suppressed not only the production of IFN-γ from CD4+ T cells and monocyte chemoattractant protein 1 (MCP-1) from CD11b+ macrophage/monocytes, but also the proliferation of these cells in vitro. Levels of both cytokines (IFN-γ and MCP-1) were also reduced in the spleen and skin of ruxolitinib-treated recipients in vivo. IFN-γ-induced MCP-1 production and migration of RAW 264.7 cells, a macrophage cell line, were inhibited by ruxolitinib. However, supplementation with MCP-1 restored this effect of ruxolitinib. In addition, blocking JAK-STAT signaling using ruxolitinib reduced the activation of STAT1 in stimulated immune effector cells. Taken together, these results suggest that ruxolitinib can prevent scl-GVHD by suppressing IFN-γ produced by T cells and MCP-1 expression in macrophage/monocytes via inhibition of JAK-STAT signaling.


Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Pirazóis/farmacologia , Animais , Doença Crônica , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Doença Enxerto-Hospedeiro/enzimologia , Janus Quinase 1/metabolismo , Janus Quinase 2/genética , Camundongos , Camundongos Endogâmicos BALB C , Nitrilas , Pirimidinas
12.
PLoS One ; 16(3): e0248011, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33662027

RESUMO

Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of wound healing. Numerous reports have established that cells from keloid scars display Warburg metabolism-a form of JAK2/STAT3-induced metabolic adaptation typical of rapidly dividing cells in which glycolysis becomes the predominant source of ATP over oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along with cells from patients with STAT3 loss of function (STA3 LOF; autosomal dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure recapitulated the exaggerated closure and hyper-glycolytic state of keloid fibroblasts through JAK1/2- and STAT3-dependent pathways. Although additional studies are needed before extrapolating from a representative cell line to keloids writ large, our results provide novel insights into the metabolic consequences of STAT3 dysfunction, suggest a possible role for folate metabolism in the pathogenesis of keloid scars, and offer in vitro pre-clinical data supporting considerations of clinical trials for ruxolitinib in keloid disorder.


Assuntos
Fibroblastos/efeitos dos fármacos , Ácido Fólico/farmacologia , Queloide/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Complexo Vitamínico B/farmacologia , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patologia , Glicólise/efeitos dos fármacos , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Queloide/tratamento farmacológico , Queloide/patologia , Nitrilas , Pirimidinas , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Chemotherapy ; 66(3): 87-91, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33784668

RESUMO

Ruxolitinib side effects include the most frequent hematological toxicity along with a more recently evidenced immunosuppressive activity, interfering both with the innate and adaptive immunity, and several cases of reactivation of latent infections by opportunistic agents in patients in treatment with ruxolitinib have been published in the last years. Several pathophysiological mechanisms may explain an association between ruxolitinib and opportunistic infections. From what we know, the only case of an isolated lymph node TBC reactivation in a ruxolitinib-treated myelofibrosis (MF) patient was reported by Patil et al. in 2016 [Int J Med Sci Public Health. 2017;6(3):1]. Other 10 cases describing TBC reactivations in MF patients assuming ruxolitinib and successfully treated with 4-drug anti-TBC therapy are available in the literature to date. The case we reported describes an isolated lymph nodal TBC reactivation in a patient with the diagnosis of post-essential thrombocythemia-MF during ruxolitinib treatment after a long course of interferon-a (IFN-α2b) assumed for the previous diagnosis of ET. The case we report teaches that lymphadenopathy with or without constitutional symptoms developing during ruxolitinib therapy should be considered as a possible manifestation of a TBC reactivation in patients with a previous positive TBC-exposure test. In these cases, Ziel-Nielsen testing on urine and sputum has to be performed to rule out infectiousness and eventually isolate the patient. Moreover, previous long-time exposition to IFN-α2b may be related with a higher risk for TBC reactivation in these subset of patients. We encourage reevaluation of the cohorts of patients treated with ruxolitinib in previous and current large prospective studies to study the possible correlation between previous exposition to IFN-α2b and TBC reactivation.


Assuntos
Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Tuberculose dos Linfonodos/etiologia , Adulto , Feminino , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Nitrilas , Mielofibrose Primária/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas , Trombocitemia Essencial/complicações , Trombocitemia Essencial/diagnóstico , Tuberculose dos Linfonodos/diagnóstico
14.
J Cell Mol Med ; 25(7): 3560-3572, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33710777

RESUMO

Recent studies have revealed that exercise has myocardial protective effects, but the exact mechanism remains unclear. Studies have increasingly found that peptides play a protective role in myocardial ischaemia-reperfusion (I/R) injury. However, little is known about the role of exercise-induced peptides in myocardial I/R injury. To elucidate the effect of exercise-induced peptide EIP-22 in myocardial I/R injury, we first determined the effect of EIP-22 on hypoxia/reperfusion (H/R)- or H2 O2 -induced injury via assessing cell viability and lactate dehydrogenase (LDH) level. In addition, reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) was assessed by fluorescence microscope. Meanwhile, Western blot and TUNEL methods were used to detect apoptosis level. Then, we conducted mice I/R injury model and verified the effect of EIP-22 by measuring cardiac function, evaluating heart pathology and detecting serum LDH, CK-MB and cTnI level. Finally, the main signalling pathway was analysed by RNA-seq. In vitro, EIP-22 treatment significantly improved cells viabilities and MMP and attenuated the LDH, ROS and apoptosis level. In vivo, EIP-22 distinctly improved cardiac function, ameliorated myocardial infarction area and fibrosis and decreased serum LDH, CK-MB and cTnI level. Mechanistically, JAK/STAT signalling pathway was focussed by RNA-seq and we confirmed that EIP-22 up-regulated the expression of p-JAK2 and p-STAT3. Moreover, AG490, a selective inhibitor of JAK2/STAT3, eliminated the protective roles of EIP-22. The results uncovered that exercise-induced peptide EIP-22 protected cardiomyocytes from myocardial I/R injury via activating JAK2/STAT3 signalling pathway and might be a new candidate molecule for the treatment of myocardial I/R injury.


Assuntos
Janus Quinase 2/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Peptídeos/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Janus Quinase 2/antagonistas & inibidores , L-Lactato Desidrogenase/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais , Tirfostinas/farmacologia
15.
Eur J Med Chem ; 216: 113333, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33689932

RESUMO

The cumulative evidence supports STAT3, a transcriptional mediator of oncogenic signaling, as a therapeutic target in cancer. The development of STAT3 inhibitors remain an active area of research as no inhibitors have yet to be approved for cancer treatment. In a continuing effort to develop more potent STAT3 inhibitors based on our previously identified hit compound 16w, a series of benzothiazole derivatives with unique binding mode in SH2 domain of STAT3 were designed, synthesized and biologically evaluated. Of note, compound B19 demonstrated excellent activity against IL-6/STAT3 signaling pathway with the IC50 value as low as 0.067 µM as determined by a luciferase reporter assay. Moreover, multiple compounds displayed potent antiproliferative activity against MDA-MB-468 and JAK2 mutant HEL cell lines. Further biochemical study using Western blot assay indicated that B19 blocked the phosphorylation of STAT3 at Tyr 705 and Ser 727 and thus suppressed STAT3-mediated gene expression of c-MYC and MCL-1. Simultaneously, it induced cancer cell G2/M phase arrest and apoptosis both in MDA-MB-468 and HEL cell lines. Finally, molecular docking study along with surface plasmon resonance (SPR) and fluorescence polarization (FP) assays disclosed the binding mode of B19 in STAT3 SH2 domain. Taken together, our finding suggests that B19 is a promising therapeutic STAT3 inhibitor for cancer treatment.


Assuntos
Antineoplásicos/química , Benzotiazóis/química , Desenho de Fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzotiazóis/metabolismo , Benzotiazóis/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Transcrição Genética/efeitos dos fármacos , Domínios de Homologia de src
16.
Biomed Pharmacother ; 137: 111373, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33761599

RESUMO

Psoriasis is a chronic, inflammatory autoimmune disease mediated by T cells, and characterized with abnormal proliferation and differentiation of keratinocytes, and inflammatory infiltration. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway has been identified to play essential roles in mediating various of biological processes, and is closely related to autoimmune diseases. Dendritic cells (DCs) are important antigen presenting cells and play an important regulatory role in T cells. The proliferation, differentiation and function of DCs are regulated by JAK and FMS-like tyrosine kinase 3 (FLT3) signal pathways. Flonoltinib maleate (FM), a high selectivity dual JAK2/FLT3 inhibitor with IC50 values of 0.8 nM and 15 nM for JAK2 and FLT3, respectively, was developed by our laboratory. Moreover, FM was a potent JAK2 inhibitor with 863-fold and 696-fold selectivity over JAK1 and JAK3, respectively. In this study, the anti-psoriasis activity of FM was evaluated both in vitro and in vivo. FM effectively inhibited the proliferation of HaCaT, the inflammatory keratinocyte induced by M5 and markedly suppressed the generation and differentiation of DCs from bone marrow (BM), and inhibited the expression of FLT3 in DCs in vitro. FM effectively inhibited the ear thickening and improved the pathological changes of the ear in interleukin (IL)-23-induced psoriasis-like acanthosis mouse model. Further in keratin 14-vascular endothelial growth factor (K14-VEGF) transgenic homozygous mice model, FM could obviously improve the psoriatic symptom and pathological changes, significantly inhibit the generations of Th1 and Th17 cells in the spleen, and the accumulations of DCs in the ears. FM could also significantly reduce the expression of various inflammatory factors both in C57BL/6 and K14-VEGF mice ears, and the serum of K14-VEGF mice. Mechanism revealed that FM effectively suppressed the phosphorylation of JAK2, STAT3 and STAT5 in inflammatory keratinocytes and the mice ears of C57BL/6 and K14-VEGF, as well as the phosphorylation of FLT3 in K14-VEGF mice ears. In conclusion, FM plays an excellent anti-psoriasis activity, including inhibiting keratinocyte proliferation and regulating inflammatory response through inhibiting JAK2 and FLT3 signaling pathway.


Assuntos
Janus Quinase 2/antagonistas & inibidores , Psoríase/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Células da Medula Óssea/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Orelha Externa/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/genética
17.
Aging (Albany NY) ; 13(6): 8248-8275, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33686952

RESUMO

This study aimed to identify effective targets for carcinogenesis of primary myelofibrosis (PMF), as well as to screen ideal lead compounds with potential inhibition effect on Janus kinase 2 to contribute to the medication design and development. Gene expression profiles of GSE26049, GSE53482, GSE61629 were obtained from the Gene Expression Omnibus database. The differentially expressed genes were identified, and functional enrichment analyses such as Gene Ontology, protein-protein interaction network etc., were performed step by step. Subsequently, highly-precise computational techniques were conducted to identify potential inhibitors of JAK2. A series of structural biology methods including virtual screening, ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction, molecule docking, molecular dynamics simulation etc., were implemented to discover novel natural compounds. Results elucidated that PMF patients had abnormal LCN2, JAK2, MMP8, CAMP, DEFA4, LTF, MPO, HBD, STAT4, EBF1 mRNA expression compared to normal patients. Functional enrichment analysis revealed that these genes were mainly enriched in erythrocyte differentiation, neutrophil degranulation and killing cells of other organisms. Two novel natural compounds, ZINC000013513540 and ZINC000004099068 were found binding to JAK2 with favorable interaction energy together with high binding affinity. They were predicted with non-Ames mutagenicity, low-rodent carcinogenicity, less developmental toxicity potential as well as non-toxicity with liver. Molecular dynamics simulation demonstrated that these two complexes: ZINC000013513540-JAK2 and ZINC000004099068-JAK2 could exist stably under natural circumstances. In conclusion, this study revealed hub genes in the carcinogenesis of PMF. ZINC000013513540 and ZINC000004099068 were promising drugs in dealing with PMF. This study may also accelerate exploration of new drugs.


Assuntos
Inibidores Enzimáticos/farmacologia , Perfilação da Expressão Gênica/métodos , Janus Quinase 2/antagonistas & inibidores , Mielofibrose Primária/enzimologia , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos
18.
Drugs ; 81(7): 771-823, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33788182

RESUMO

The proliferation of targeted anticancer agents over the last two decades has revolutionized cancer treatment and improved survival in many previously refractory malignancies. However, many agents are associated with characteristic ophthalmic adverse effects. It is important that ophthalmologists recognize and maintain a high index of suspicion for these side effects in patients on targeted therapy. Most ophthalmic adverse effects can be treated with specific ocular therapy without discontinuation of cancer treatment, although it is important to be aware of the life-threatening and vision-threatening circumstances that would require therapy cessation in conjunction with the patient's oncologist. This review aims to summarize the ophthalmic adverse effects of targeted and hormonal anticancer agents and briefly describe their management.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Olho/efeitos dos fármacos , Neuropatia Óptica Tóxica/epidemiologia , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Ensaios Clínicos como Assunto , Receptores ErbB/antagonistas & inibidores , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Janus Quinase 2/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Índice de Gravidade de Doença , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
19.
Life Sci ; 271: 119197, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33577847

RESUMO

AIMS: To investigate the improvement and mechanisms of silymarin on renal injury in mouse podocytes and streptozotocin (STZ)-induced diabetic nephropathy model (DN) rats. MAIN METHODS: Firstly, the effects of silymarin on the cell viability and cellular injury-related indicators of high-glucose incubated mouse podocytes MPC-5 were assessed by CCK-8 and western blotting (WB) methods, respectively. The STZ-induced diabetic rats with DN were treated with silymarin nanoliposomes at three doses for consecutive 8-week. General metabolic indicators, renal functions and lipid accumulation-related factors were all measured. The renal tissue sections were stained and observed via hematoxylin-eosin (H&E) staining method. Real-time RT-PCR and WB methods were utilized to measure the expression of JAK2/STAT3/SOCS1 and TGF-ß/Smad signaling pathway related factors. KEY FINDINGS: Silymarin significantly improve the high-glucose induced up-regulation of podoxin and nephrin, as well as the expression of inflammatory cytokines IL-6, ICAM-1 and TNF-α, and the cell survival rates were also significantly increased in a dose-dependent manner. Significant improvement on body weight/kidney ratio, renal functions and lipid profiles in renal tissues were observed in STZ-induced diabetic rats after chronic silymarin treatment. The H&E staining exhibited that the pathological damages in renal tissues were obviously improved. Moreover, silymarin nanoliposomes treatment notably suppressed expression levels of inflammation-related proteins as well as IL-6 and ICAM-1, and regulated JAK2/STAT3/SOCS1 and TGF-ß/Smad signaling pathway, thereby exhibited protective effects on kidney of DN model rats. SIGNIFICANCE: Silymarin nanoliposomes ameliorate STZ-induced kidney injury by improving oxidative stress, renal fibrosis, and co-inhibiting JAK2/STAT3/SOCS1 and TGF-ß/Smad signaling pathways in diabetic rats.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Janus Quinase 2/antagonistas & inibidores , Nanopartículas/administração & dosagem , Fator de Transcrição STAT3/antagonistas & inibidores , Silimarina/administração & dosagem , Proteína 1 Supressora da Sinalização de Citocina/antagonistas & inibidores , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Antioxidantes/administração & dosagem , Linhagem Celular , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Janus Quinase 2/metabolismo , Lipossomos , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteínas Smad/antagonistas & inibidores , Proteínas Smad/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Fator de Crescimento Transformador beta/metabolismo
20.
J Med Chem ; 64(4): 2228-2241, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33570945

RESUMO

The discovery that aberrant activity of Janus kinase 2 (JAK2) is a driver of myeloproliferative neoplasms (MPNs) has led to significant efforts to develop small molecule inhibitors for this patient population. Ruxolitinib and fedratinib have been approved for use in MPN patients, while baricitinib, an achiral analogue of ruxolitinib, has been approved for rheumatoid arthritis. However, structural information on the interaction of these therapeutics with JAK2 remains unknown. Here, we describe a new methodology for the large-scale production of JAK2 from mammalian cells, which enabled us to determine the first crystal structures of JAK2 bound to these drugs and derivatives thereof. Along with biochemical and cellular data, the results provide a comprehensive view of the shape complementarity required for chiral and achiral inhibitors to achieve highest activity, which may facilitate the development of more effective JAK2 inhibitors as therapeutics.


Assuntos
Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirrolidinas/farmacologia , Sulfonamidas/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Janus Quinase 2/metabolismo , Estrutura Molecular , Nitrilas , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Pirimidinas , Pirrolidinas/química , Pirrolidinas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismo
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