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1.
Int J Mol Sci ; 22(24)2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34948183

RESUMO

The impact of new and emerging therapies on the microenvironment of primary cutaneous lymphomas (PCLs) has been recently raised in the literature. Concomitantly, novel treatments are already used or registered (dupilumab, upadacitinib) and others seem to be added to the armamentarium against atopic dermatitis. Our aim was to review the literature on interleukins 4, 13, 22, and 31, and JAK/STAT pathways in PCLs to elucidate the safety of using biologics (dupilumab, tralokinumab, fezakinumab, nemolizumab) and small molecule inhibitors (upadacitinib, baricitinib, abrocitinib, ruxolitinib, tofacitinib) in the treatment of atopic dermatitis. We summarized the current state of knowledge on this topic based on the search of the PubMed database and related references published before 21 October 2021. Our analysis suggests that some of the mentioned agents (dupilumab, ruxolitinib) and others may have a direct impact on the progression of cutaneous lymphomas. This issue requires further study and meticulous monitoring of patients receiving these drugs to ensure their safety, especially in light of the FDA warning on tofacitinib. In conclusion, in the case of the rapid progression of atopic dermatitis/eczema, especially in patients older than 40 years old, there is a necessity to perform a biopsy followed by a very careful pathological examination.


Assuntos
Dermatite Atópica/tratamento farmacológico , Linfoma Anaplásico Cutâneo Primário de Células Grandes/etiologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Dermatite Atópica/patologia , Humanos , Interleucinas/metabolismo , Janus Quinases/metabolismo , Linfoma/etiologia , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Piperidinas/farmacologia , Purinas/farmacologia , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/etiologia , Sulfonamidas/farmacologia , Microambiente Tumoral/efeitos dos fármacos
2.
Mol Syst Biol ; 17(9): e10426, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34486798

RESUMO

Although 15-20% of COVID-19 patients experience hyper-inflammation induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N-terminal domain (NTD) of the SARS-CoV-2 spike protein substantially induces multiple inflammatory molecules in myeloid cells and human PBMCs. Using a combination of phenotypic screening with machine learning-based modeling, we identified and experimentally validated several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as essential downstream mediators of NTD-induced cytokine production, implicating the role of multiple signaling pathways in cytokine release. Further, we found several FDA-approved drugs, including ponatinib, and cobimetinib as potent inhibitors of the NTD-mediated cytokine release. Treatment with ponatinib outperforms other drugs, including dexamethasone and baricitinib, inhibiting all cytokines in response to the NTD from SARS-CoV-2 and emerging variants. Finally, ponatinib treatment inhibits lipopolysaccharide-mediated cytokine release in myeloid cells in vitro and lung inflammation mouse model. Together, we propose that agents targeting multiple kinases required for SARS-CoV-2-mediated cytokine release, such as ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19.


Assuntos
Antivirais/farmacologia , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Animais , Azetidinas/farmacologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Janus Quinase 1/metabolismo , Lipopolissacarídeos/toxicidade , Aprendizado de Máquina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/virologia , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Pirazóis/farmacologia , Piridazinas/farmacologia , Células RAW 264.7 , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Sulfonamidas/farmacologia
3.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360797

RESUMO

A novel series of N-substituted cis- and trans-3-aryl-4-(diethoxyphosphoryl)azetidin-2-ones were synthesized by the Kinugasa reaction of N-methyl- or N-benzyl-(diethyoxyphosphoryl)nitrone and selected aryl alkynes. Stereochemistry of diastereoisomeric adducts was established based on vicinal H3-H4 coupling constants in azetidin-2-one ring. All the obtained azetidin-2-ones were evaluated for the antiviral activity against a broad range of DNA and RNA viruses. Azetidin-2-one trans-11f showed moderate inhibitory activity against human coronavirus (229E) with EC50 = 45 µM. The other isomer cis-11f was active against influenza A virus H1N1 subtype (EC50 = 12 µM by visual CPE score; EC50 = 8.3 µM by TMS score; MCC > 100 µM, CC50 = 39.9 µM). Several azetidin-2-ones 10 and 11 were tested for their cytostatic activity toward nine cancerous cell lines and several of them appeared slightly active for Capan-1, Hap1 and HCT-116 cells values of IC50 in the range 14.5-97.9 µM. Compound trans-11f was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant S. aureus strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3R,4S)-11f can be responsible for the promising activity due to the potency in displacing oxacillin at ß-lactamase, thus protecting the antibiotic from undesirable biotransformation.


Assuntos
Adjuvantes Farmacêuticos/química , Adjuvantes Farmacêuticos/farmacologia , Antivirais/química , Antivirais/farmacologia , Azetidinas/farmacologia , Infecções/tratamento farmacológico , Antibacterianos/química , Antibacterianos/farmacologia , Azetidinas/química , Proteínas de Bactérias/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Coronavirus Humano 229E/efeitos dos fármacos , Citostáticos/química , Citostáticos/farmacologia , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Simulação de Dinâmica Molecular , Oxacilina/química , Proteínas de Ligação às Penicilinas/química , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo , beta-Lactamases/química
4.
Medicine (Baltimore) ; 100(30): e26739, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397713

RESUMO

ABSTRACT: Baricitinib is a Janus kinase (JAK) inhibitor that selectively blocks against JAK1 and JAK2 signaling. This study aimed to determine the effect of baricitinib on disease activity based on musculoskeletal ultrasound in patients with rheumatoid arthritis (RA).A total of 20 patients with RA receiving baricitinib for 24 weeks were assessed. Ultrasound scores of gray scale and power Doppler synovitis, joint effusion, and bone erosion in each patient were assessed between baseline and 24 weeks for 27 affected joints. Disease activity in RA was evaluated using the disease activity score for 28-joint count with erythrocyte sediment rate (DAS28-ESR), simplified disease activity index (SDAI), and clinical disease activity index (CDAI).Treatment with baricitinib for 12 weeks and 24 weeks significantly decreased disease activity composites such as DAS28-ESR, SDAI, and CDAI (P < .001 for all). Treatment with baricitinib for 24 weeks improved ultrasound-detected gray-scale and power Doppler synovitis and joint effusion compared to baseline (P = .002, P = .030, and P = .002, respectively). Bone erosion scores were not different between baseline and 24 weeks (P = .317). There were no differences in ultrasound abnormalities for improvement based on DAS28-ESR. Changes in power Doppler score were significantly associated with changes in DAS28-ESR (ß = 0.590, P = .044), but not SDAI and CDAI.This study demonstrates that baricitinib treatment has a favorable effect on ultrasound-detected abnormalities including synovitis and bone erosion in patients with RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Sinovite/tratamento farmacológico , Artrite Reumatoide/diagnóstico por imagem , Azetidinas/farmacologia , Osso e Ossos/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Purinas/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Sinovite/diagnóstico por imagem , Ultrassonografia
5.
Front Immunol ; 12: 672461, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248953

RESUMO

Objectives: Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis. Janus Kinase inhibitors (JAKi) have emerged as an encouraging class of drugs for the treatment of PsA. Here, we compare the effect of four JAKi on primary PsA synovial fibroblasts (PsAFLS) activation, metabolic function, and invasive and migratory capacity. Methods: Primary PsAFLS were isolated and cultured with JAKi (Peficitinib, Filgotinib, Baricitinib and Upadacitinib) in the presence of Oncostatin M (OSM). pSTAT3 expression in response to OSM was quantified by Western Blot analysis. Pro-inflammatory cytokines/chemokines were quantified by ELISA and cell migration by wound-repair scratch assays. Invasive capacity was examined using Matrigel™ invasion chambers and MMP multiplex MSD assays. PsAFLS bioenergetics was assessed using the Seahorse XFe Extracellular Flux Analyzer, which simultaneously quantifies two energetic pathways- glycolysis (ECAR) and oxidative phosphorylation (OCR). In parallel, inflammatory, invasive, and migratory genes were quantified by RT-PCR. Results: OSM induces pSTAT3 expression in PsAFLS. OSM-induced secretion of MCP-1 and IL-6 was inhibited by all JAKi with Peficitinib, Baricitinib and Upadacitinib showing the greatest effect. In contrast, JAKi had no significant impact on IL-8 expression in response to OSM. PsAFLS cell invasion, migratory capacity and MMP1, 3, and 9 were suppressed following JAKi treatment, with Peficitinib showing the greatest effect. These functional effects were accompanied by a change in the cellular bioenergetic profile of PsAFLS, where JAKi significantly decreased glycolysis and the ECAR/OCR, resulting in a shift to a more quiescent phenotype, with Peficitinib demonstrating the most pronounced effect. Conclusion: This study demonstrates that JAK/STAT signalling mediates the complex interplay between inflammation and cellular metabolism in PsA pathogenesis. This inhibition shows effective suppression of inflammatory mechanisms that drive pathogenic functions of PsAFLS, further supporting the role of JAKi as a therapeutic target for the treatment of PsA.


Assuntos
Artrite Psoriásica , Fibroblastos/efeitos dos fármacos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Fatores de Transcrição STAT/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/farmacologia , Adulto , Idoso , Artrite Psoriásica/imunologia , Artrite Psoriásica/metabolismo , Azetidinas/farmacologia , Células Cultivadas , Feminino , Fibroblastos/enzimologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Purinas/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Membrana Sinovial/efeitos dos fármacos , Triazóis/farmacologia
6.
Molecules ; 26(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202191

RESUMO

Twenty-two novel, variously substituted nitroazetidines were designed as both sulfonamide and urethane vinylogs possibly endowed with antimicrobial activity. The compounds under study were obtained following a general procedure recently developed, starting from 4-nitropentadienoates deriving from a common ß-nitrothiophenic precursor. While being devoid of any activity against fungi and Gram-negative bacteria, most of the title compounds performed as potent antibacterial agents on Gram-positive bacteria (E. faecalis and three strains of S. aureus), with the most potent congener being the 1-(4-chlorobenzyl)-3-nitro-4-(p-tolyl)azetidine 22, which displayed potency close to that of norfloxacin, the reference antibiotic (minimum inhibitory concentration values 4 and 1-2 µg/mL, respectively). Since 22 combines a relatively efficient activity against Gram-positive bacteria and a cytotoxicity on eucharyotic cells only at 4-times higher concentrations (inhibiting concentration on 50% of the cultured eukaryotic cells: 36 ± 10 µM, MIC: 8.6 µM), it may be considered as a promising hit compound for the development of a new series of antibacterials selectively active on Gram-positive pathogens. The relatively concise synthetic route described herein, based on widely available starting materials, could feed further structure-activity relationship studies, thus allowing for the fine investigation and optimization of the toxico-pharmacological profile.


Assuntos
Antibacterianos , Azetidinas , Enterococcus faecalis/crescimento & desenvolvimento , Staphylococcus aureus/crescimento & desenvolvimento , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Azetidinas/síntese química , Azetidinas/química , Azetidinas/farmacologia , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Células Hep G2 , Humanos , Relação Estrutura-Atividade
7.
Cells ; 10(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202258

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is a segmental premature aging disease caused by a mutation in LMNA. The mutation generates a truncated and farnesylated form of prelamin A, called progerin. Affected individuals develop several features of normal aging, including lipodystrophy caused by the loss of general subcutaneous fat. To determine whether premature cellular senescence is responsible for the altered adipogenesis in patients with HGPS, we evaluated the differentiation of HGPS skin-derived precursor stem cells (SKPs) into adipocytes. The SKPs were isolated from primary human HGPS and normal fibroblast cultures, with senescence of 5 and 30%. We observed that the presence of high numbers of senescent cells reduced SKPs' adipogenic differentiation potential. Treatment with baricitinib, a JAK-STAT inhibitor, ameliorated the ability of HGPS SKPs to differentiate into adipocytes. Our findings suggest that the development of lipodystrophy in patients with HGPS may be associated with an increased rate of cellular senescence and chronic inflammation.


Assuntos
Lamina Tipo A/metabolismo , Progéria/patologia , Pele/patologia , Células-Tronco/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia/efeitos dos fármacos , Adolescente , Animais , Azetidinas/farmacologia , Compostos de Boro , Diferenciação Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Interleucina-8/metabolismo , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Masculino , Camundongos , PPAR gama/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Pirazóis/farmacologia , Células-Tronco/efeitos dos fármacos , Sulfonamidas/farmacologia
8.
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
9.
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
10.
Neurology ; 97(7): e673-e683, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34088874

RESUMO

OBJECTIVE: To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600-mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort. METHODS: We performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated BRAF V600-mutant GGNTs treated with RAFi/MEKi. RESULTS: Twenty-eight adults with recurrent or disseminated BRAF V600-mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p = 0.047). Responders had better KPS score (p = 0.018) and tended to be younger (p = 0.061) and to be treated earlier (p = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival. CONCLUSIONS: Our study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with BRAF V600-mutant GGNTs and encourages rechallenge in responders. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for adult patients with BRAF V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Avaliação de Resultados em Cuidados de Saúde , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Azetidinas/farmacologia , Neoplasias Encefálicas/genética , Bases de Dados Factuais , Feminino , Ganglioglioma/tratamento farmacológico , Ganglioglioma/genética , Glioma/genética , Humanos , Imidazóis/farmacologia , Avaliação de Estado de Karnofsky , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Oximas/farmacologia , Piperidinas/farmacologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridonas/farmacologia , Pirimidinonas/farmacologia , Estudos Retrospectivos , Vemurafenib/farmacologia , Quinases raf/antagonistas & inibidores
11.
J Nanobiotechnology ; 19(1): 165, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059068

RESUMO

BACKGROUND: Overexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast cancer (BRCA), especially triple-negative breast cancer (TNBC). Hence, novel treatment strategy is urgently needed. RESULTS: We found sphingosine 1 phosphate receptor 1 (S1PR1) can regulate P-STAT3/VEGFA. Database showed S1PR1 is highly expressed in BRCA and causes the poor prognosis of patients. Interrupting the expression of S1PR1 could inhibit the growth of human breast cancer cells (MCF-7 and MDA-MB-231) and suppress the angiogenesis of human umbilical vein endothelial cells (HUVECs) via affecting S1PR1/P-STAT3/VEGFA axis. Siponimod (BAF312) is a selective antagonist of S1PR1, which inhibits tumor growth and angiogenesis in vitro by downregulating the S1PR1/P-STAT3/VEGFA axis. We prepared pH-sensitive and tumor-targeted shell-core structure nanoparticles, in which hydrophilic PEG2000 modified with the cyclic Arg-Gly-Asp (cRGD) formed the shell, hydrophobic DSPE formed the core, and CaP (calcium and phosphate ions) was adsorbed onto the shell; the nanoparticles were used to deliver BAF312 (BAF312@cRGD-CaP-NPs). The size and potential of the nanoparticles were 109.9 ± 1.002 nm and - 10.6 ± 0.056 mV. The incorporation efficacy for BAF312 was 81.4%. Results confirmed BAF312@cRGD-CaP-NP could dramatically inhibit tumor growth and angiogenesis in vitro and in MDA-MB-231 tumor-bearing mice via downregulating the S1PR1/P-STAT3/VEGFA axis. CONCLUSIONS: Our data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis.


Assuntos
Indutores da Angiogênese/farmacologia , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Nanopartículas/química , Fator de Transcrição STAT3/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Azetidinas/química , Compostos de Benzil/química , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fator de Transcrição STAT3/genética , Receptores de Esfingosina-1-Fosfato/genética , Neoplasias de Mama Triplo Negativas/genética , Fator A de Crescimento do Endotélio Vascular/genética
12.
J Med Chem ; 64(11): 7261-7271, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34043360

RESUMO

After extensive screening of aerospace compounds in an effort to source a novel anticancer agent, RRx-001, a first-in-class dinitroazetidine small molecule, was selected for advancement into preclinical and clinical development. RRx-001 is a minimally toxic small molecule with a distinct chemical structure and mechanism of action. The paradox of RRx-001 is that it mediates both antitumor cytotoxicity and normal tissue protection. The question of exactly how RRx-001 does this, and by means of what mechanism(s), depending on the route of delivery, intravenous or intratumoral, are explored. RRx-001 is currently in phase 2 and 3 clinical trials for the treatment of multiple solid tumor malignancies and as a supportive care drug.


Assuntos
Antineoplásicos/química , Azetidinas/química , Antígeno CD47/metabolismo , Nitrocompostos/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Antígeno CD47/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Meia-Vida , Humanos , Morte Celular Imunogênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Nitrocompostos/farmacologia , Nitrocompostos/uso terapêutico , Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas c-myc/genética , Relação Estrutura-Atividade , Transplante Heterólogo , Macrófagos Associados a Tumor/citologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo
13.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946824

RESUMO

Red blood cells (RBCs) serve a variety of functions beyond mere oxygen transport both in health and pathology. Notably, RRx-001, a minimally toxic pleiotropic anticancer agent with macrophage activating and vascular normalization properties currently in Phase III trials, induces modification to RBCs which could promote vascular adhesion similar to sickle cells. This study assessed whether RBCs exposed to RRx-001 adhere to the tumor microvasculature and whether this adhesion alters tumor viability. We next investigated the biomechanics of RBC adhesion in the context of local inflammatory cytokines after treatment with RRx-001 as a potential mechanism for preferential tumor aggregation. Human HEP-G2 and HT-29 tumor cells were subcutaneously implanted into nu/nu mice and were infused with RRx-001-treated and Technetium-99m (99mTc)-labeled blood. RBC adhesion was quantified in an in vitro human umbilical vein endothelial cell (HUVEC) assay under both normoxic and hypoxic conditions with administration of either lipopolysaccharide (LPS) or Tumor necrosis alpha (TNFα) to mimic the known inflammation in the tumor microenvironment. One hour following administration of 99mTc labeled RBCs treated with 10 mg/kg RRx-001, we observed an approximate 2.0-fold and 1.5-fold increase in 99mTc-labeled RBCs compared to vehicle control in HEPG2 and HT-29 tumor models, respectively. Furthermore, we observed an approximate 40% and 36% decrease in HEP-G2 and HT-29 tumor weight, respectively, following treatment with RRx-001. To quantify RBC adhesive potential, we determined τ50, or the shear stress required for 50% disassociation of RBCs from HUVECs. After administration of TNF-α under normoxia, τ50 was determined to be 4.5 dynes/cm2 (95% CI: 4.3-4.7 dynes/cm2) for RBCs treated with 10 µM RRx-001, which was significantly different (p < 0.05) from τ50 in the absence of treatment. Under hypoxic conditions, the difference of τ50 with (4.8 dynes/cm2; 95% CI: 4.6-5.1 dynes/cm2) and without (2.6 dynes/cm2; 95% CI: 2.4-2.8 dynes/cm2) 10 µM RRx-001 treatment was exacerbated (p = 0.05). In conclusion, we demonstrated that RBCs treated with RRx-001 preferentially aggregate in HEP-G2 and HT-29 tumors, likely due to interactions between RRx-001 and cysteine residues within RBCs. Furthermore, RRx-001 treated RBCs demonstrated increased adhesive potential to endothelial cells upon introduction of TNF-α and hypoxia suggesting that RRx-001 may induce preferential adhesion in the tumor but not in other tissues with endothelial dysfunction due to conditions prevalent in older cancer patients such as heart disease or diabetic vasculopathy.


Assuntos
Antineoplásicos/farmacologia , Azetidinas/farmacologia , Células Endoteliais/citologia , Membrana Eritrocítica/efeitos dos fármacos , Nitrocompostos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Azetidinas/uso terapêutico , Adesão Celular/efeitos dos fármacos , Hipóxia Celular , Cisteína/química , Citocinas/metabolismo , Células Endoteliais/química , Agregação Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/química , Células HT29/transplante , Células Hep G2/transplante , Células Endoteliais da Veia Umbilical Humana , Humanos , Lipopolissacarídeos/farmacologia , Lipídeos de Membrana/biossíntese , Camundongos , Camundongos Nus , Neoplasias/irrigação sanguínea , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/tratamento farmacológico , Nitrocompostos/uso terapêutico , Fosfatidilserinas/biossíntese , Receptores de Superfície Celular/biossíntese , Resistência ao Cisalhamento , Microambiente Tumoral , Fator de Necrose Tumoral alfa/farmacologia
14.
Eur J Med Chem ; 221: 113531, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34044345

RESUMO

Organoselenium compounds have attracted growing interests as promising antitumor agents over recent years. Herein, four series of novel selenium-containing chiral 1,4-diarylazetidin-2-ones were asymmetrically synthesized and biologically evaluated for antitumor activities. Among them, compound 7 was found to be about 10-fold more potent than its prototype compound 1a, and compound 9a exhibited the most potent cytotoxicity against five human cancer cell lines, including a paclitaxel-resistant human ovarian cancer cell line A2780T, with IC50 values ranging from 1 to 3 nM. Mechanistic studies revealed that compound 9a worked by disrupting tubulin polymerization, inducing reactive oxygen species (ROS) production, decreasing mitochondrial membrane potential, blocking the cell cycle in the G2/M phase, inducing cellular apoptosis and suppressing angiogenesis. Additionally, compound 9a exhibited appropriate human-microsomal metabolic stability and physicochemical properties. Importantly, compound 9a was found to inhibit tumor growth effectively in a xenograft mice model with low toxicity profile, which rendered 9a a highly promising candidate for further pre-clinical development.


Assuntos
Antineoplásicos/farmacologia , Azetidinas/farmacologia , Compostos Organosselênicos/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Azetidinas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Polimerização/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
15.
J Clin Pharmacol ; 61(10): 1274-1285, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33870531

RESUMO

Baricitinib is a JAK1/2 inhibitor that was first approved for treating moderate to severe rheumatoid arthritis (RA) but that later showed considerable efficacy in the control of exaggerated inflammatory responses that occur in a wide range of diseases. There is a growing body of evidence, obtained from clinical trials and case reports, demonstrating clinical and paraclinical improvement in patients following administration of baricitinib including RA, systemic lupus erythematosus, psoriasis, atopic dermatitis, alopecia areata, interferon-mediated autoinflammatory diseases, graft-versus-host disease, diabetic kidney disease, and, recently, coronavirus disease-19. However, despite overall encouraging results, many adverse effects have been observed in baricitinib-treated patients, ranging from simple infections to increased risk of malignancies, particularly in long-term use. The significant efficacy of baricitinib, versus the probable adverse effects, urge further investigation before establishing it as a part of standard therapeutic protocols. Here, we have provided a review of the studies that have used baricitinib for treating various inflammatory disorders and summarized the advantages and disadvantages of its administration.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Azetidinas/farmacologia , COVID-19 , Inflamação/tratamento farmacológico , Purinas/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , COVID-19/tratamento farmacológico , COVID-19/imunologia , Humanos , Inibidores de Janus Quinases/farmacologia , Medição de Risco , SARS-CoV-2 , Resultado do Tratamento
16.
Vet Parasitol ; 293: 109430, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33901932

RESUMO

Ectoparasite infestations are not common in degus. Two cases are presented here where use of Stronghold® Plus/Revolution® Plus (selamectin and sarolaner topical solution) was successfully administered to a degu (Octodon degus) for treatment of naturally-occurring mite infesations. Selamectin (Stronghold®/Revolution®) has been demonstrated to be effective against naturally-occurring mite infections in dogs and selamectin is approved for use in dogs for the treatment of sarcoptic mange (caused by Sarcoptes scabiei) at a dose of 6 mg/kg. In the first case, a 2.6-years-old female degu housed in a group with four other degus was presented with pruritic skin reactions, restlessness and hairloss. Mites morphologically similar to Demodex sp. were detected in the deep skin scrapings. All four degus were treated with Stronghold® Plus/Revolution® Plus (30 mg/kg selamectin and 5 mg/kg sarolaner) once a week for a total of six treatments. The spot-on was administered topically on the dorsal cervical region. Following treatment the degu presenting with clinical signs showed a rapid improvement with the pruritus and overall dermatitis resolving within 2 weeks of treatment. Skin scrapes and microscopic examination of epidermal debris collected from the affected degu were negative for mites from day 14 onwards. In the second case, a group of four 4-6.5-years-old female and male degus that were housed together were infested with Ornithonyssus bacoti. All animals were treated with 30 mg/kg selamectin and 5 mg/kg sarolaner in four total weekly doses. One week later no living mites were found on the patients or in their environment. The four degus improved visibly, and within three weeks of treatment the skin lesions associated with the infestation subsided. The antiparasiticides showed a satisfactory efficacy and were well tolerated (n = 9 animals treated in a total).


Assuntos
Azetidinas , Ivermectina/análogos & derivados , Infestações por Ácaros , Octodon , Doenças dos Roedores , Compostos de Espiro , Administração Tópica , Animais , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Feminino , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Masculino , Infestações por Ácaros/tratamento farmacológico , Infestações por Ácaros/veterinária , Ácaros/efeitos dos fármacos , Octodon/parasitologia , Doenças dos Roedores/tratamento farmacológico , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Resultado do Tratamento
17.
Front Immunol ; 12: 650708, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33927721

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) and a CD4+ T cell-mediated autoimmune disease. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is recognized as the major mechanism that regulates the differentiation and function of T helper (Th) 1 and Th17 cells, which are recognized as pivotal effector cells responsible for the development of EAE. We used baricitinib, a JAK 1/2 inhibitor, to investigate the therapeutic efficacy of inhibiting the JAK/STAT pathway in EAE mice. Our results showed that baricitinib significantly delayed the onset time, decreased the severity of clinical symptoms, shortened the duration of EAE, and alleviated demyelination and immune cell infiltration in the spinal cord. In addition, baricitinib treatment downregulated the proportion of interferon-γ+CD4+ Th1 and interleukin-17+CD4+ Th17 cells, decreased the levels of retinoic acid-related orphan receptor γ t and T-bet mRNA, inhibited lymphocyte proliferation, and decreased the expression of proinflammatory cytokines and chemokines in the spleen of mice with EAE. Furthermore, our results showed the role of baricitinib in suppressing the phosphorylation of STATs 1, 3, and 4 in the spleen of EAE mice. Therefore, our study demonstrates that baricitinib could potentially alleviate inflammation in mice with EAE and may be a promising candidate for treating MS.


Assuntos
Azetidinas/farmacologia , Encefalomielite Autoimune Experimental/prevenção & controle , Janus Quinases/antagonistas & inibidores , Purinas/farmacologia , Pirazóis/farmacologia , Fatores de Transcrição STAT/imunologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Administração Oral , Animais , Azetidinas/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Janus Quinases/imunologia , Janus Quinases/metabolismo , Camundongos Endogâmicos C57BL , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/imunologia , Sulfonamidas/administração & dosagem
18.
J Med Chem ; 64(6): 2953-2966, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33682420

RESUMO

Nav1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 (1) and GDC-0310 (2), selective Nav1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3. This resulted in the discovery of GDC-0276 (1), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Nav1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Nav selectivity and pharmacokinetic profile over 1.


Assuntos
Azetidinas/farmacologia , Benzamidas/farmacologia , Descoberta de Drogas , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Sulfonamidas/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Azetidinas/química , Azetidinas/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Células Cultivadas , Células HEK293 , Humanos , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ratos Sprague-Dawley , Sulfonamidas/química , Sulfonamidas/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética
19.
Ann Rheum Dis ; 80(7): 865-875, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33741556

RESUMO

OBJECTIVE: Janus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK family member selectivity. Filgotinib was compared with baricitinib, tofacitinib and upadacitinib to elucidate the pharmacological basis underlying its clinical efficacy and safety. METHODS: In vitro JAKinib inhibition of signal transducer and activator of transcription phosphorylation (pSTAT) was measured by flow cytometry in peripheral blood mononuclear cells and whole blood from healthy donors and patients with RA following cytokine stimulation of distinct JAK/STAT pathways. The average daily pSTAT and time above 50% inhibition were calculated at clinical plasma drug exposures in immune cells. The translation of these measures was evaluated in ex vivo-stimulated assays in phase 1 healthy volunteers. RESULTS: JAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type. JAK1-dependent pathways (interferon (IFN)α/pSTAT5, interleukin (IL)-6/pSTAT1) were among the most potently inhibited by all JAKinibs in healthy and RA blood, with filgotinib exhibiting the greatest selectivity for JAK1 pathways. Filgotinib (200 mg once daily) had calculated average daily target inhibition for IFNα/pSTAT5 and IL-6/pSTAT1 that was equivalent to tofacitinib (5 mg two times per day), upadacitinib (15 mg once daily) and baricitinib (4 mg once daily), with the least average daily inhibition for the JAK2-dependent and JAK3-dependent pathways including IL-2, IL-15, IL-4 (JAK1/JAK3), IFNγ (JAK1/JAK2), granulocyte colony stimulating factor, IL-12, IL-23 (JAK2/tyrosine kinase 2) and granulocyte-macrophage colony-stimulating factor (JAK2/JAK2). Ex vivo pharmacodynamic data from phase 1 healthy volunteers clinically confirmed JAK1 selectivity of filgotinib. CONCLUSION: Filgotinib inhibited JAK1-mediated signalling similarly to other JAKinibs, but with less inhibition of JAK2-dependent and JAK3-dependent pathways, providing a mechanistic rationale for its apparently differentiated efficacy:safety profile.


Assuntos
Antirreumáticos/farmacologia , Citocinas/efeitos dos fármacos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/efeitos dos fármacos , Piridinas/farmacologia , Triazóis/farmacologia , Artrite Reumatoide , Azetidinas/farmacologia , Células Cultivadas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Piperidinas/farmacologia , Purinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia
20.
Biol Pharm Bull ; 44(2): 188-196, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33518672

RESUMO

ONO-4641, 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid (ceralifimod), is a second-generation sphingosine 1-phosphate receptor agonist selective for sphingosine 1-phosphate receptors 1 and 5, and has clinical effects in multiple sclerosis. The objective of the present study was to explore other potential indications for ONO-4641 based on its immunomodulatory effects. ONO-4641 was tested in non-obese diabetic (NOD) mice, an animal model of spontaneous type 1 diabetes mellitus, an autoimmune disease with unmet medical needs. ONO-4641 at a dose of 0.1 mg/kg prevented the onset of diabetes mellitus in NOD mice. Furthermore, ONO-4641 at doses of 0.03 and 0.1 mg/kg decreased diabetic prevalence in NOD mice after the onset of diabetes mellitus in a dose-dependent manner. Histopathological analysis demonstrated that insulin-positive areas in the islets of mice administered 0.03 and 0.1 mg/kg ONO-4641 showed a tendency of high values although they were not significantly different from the Control group, which was treated with vehicle. These observations suggest ONO-4641 may delay the onset and progression of type 1 diabetes mellitus.


Assuntos
Azetidinas/farmacologia , Diabetes Mellitus Tipo 1/prevenção & controle , Naftalenos/farmacologia , Receptores de Esfingosina-1-Fosfato/agonistas , Animais , Azetidinas/uso terapêutico , Glicemia/análise , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/patologia , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Camundongos , Camundongos Endogâmicos NOD , Naftalenos/uso terapêutico
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