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1.
Chem Biol Interact ; 352: 109779, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-34922904

RESUMO

Growing evidence shows that cancer progression links with both heterogeneity of the tumor microenvironment and dysregulated activity of immune cells. Cancer-secreted exosomes are being recognized as indispensable mediators of the exchange cargo between cancer and immune cells. The M2-phenotype tumor-associated macrophages have the function of promoting tumor progression and drug resistance. Diffuse large B-cell lymphoma(DLBCL) is a highly heterogeneous and very common malignant non-Hodgkin's lymphoma. Here, we demonstrate that different subtype DLBCL cell-derived exosomes are internalized by macrophages, which can affect macrophages polarization. The mechanism of DLBCL-derived exosomes on macrophage polarization remains unclear currently. This study showed that DLBCL-secreted exosomes could induce the transformation of macrophages to a protumor M2-like phenotype, and block the drug-induced apoptosis of DLBCL cells in an indirect co-culture system. Different DLBCL-derived exosomes could change the phenotype of macrophages through the STAT3 signaling, which upregulated the expression of oncogenic genes and classical markers of M2-like phenotype macrophages, such as IL-10, CD206, and CD163. The addition of DLBCL-derived exosomes resulted in the activation of the STAT3 signaling pathway of M0/M2 macrophages in an indirect co-culture system. GP130 was highly enriched in DLBCL-derived exosomes, which triggered the activation of STAT3 of macrophages and subsequently induced the downstream targets such as BCL2, SURVIVIN, and BAX. The parallel changes of STAT3 and GP130 in macrophages confirmed that GP130 of DLBCL-derived exosomes promoted macrophage polarization by activating STAT3 signaling. Furthermore, all of these effects could be reversed by the GP130 inhibitor SC144. The data indicated that DLBCL-derived exosomes could trigger macrophages polarization into a pro-survival M2-like phenotype, which was at least partially through the GP130/STAT3 signaling pathway. Collectively, this study showed that DLBCL-derived exosomes could promote macrophages transformation to protumor M2-like phenotype in the tumor microenvironment.


Assuntos
Receptor gp130 de Citocina/imunologia , Exossomos/imunologia , Exossomos/metabolismo , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/metabolismo , Fator de Transcrição STAT3/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Linhagem Celular Tumoral , Receptor gp130 de Citocina/antagonistas & inibidores , Humanos , Hidrazinas/farmacologia , Imunofenotipagem , Modelos Biológicos , Fenótipo , Quinoxalinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/classificação
2.
J Enzyme Inhib Med Chem ; 36(1): 1810-1828, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34338135

RESUMO

Novel quinazolinones conjugated with indole acetamide (4a-c), ibuprofen (7a-e), or thioacetohydrazide (13a,b, and 14a-d) were designed to increase COX-2 selectivity. The three synthesised series exhibited superior COX-2 selectivity compared with the previously reported quinazolinones and their NSAID analogue and had equipotent COX-2 selectivity as celecoxib. Compared with celecoxib, 4 b, 7c, and 13 b showed similar anti-inflammatory activity in vivo, while 13 b and 14a showed superior inhibition of the inflammatory mediator nitric oxide, and 7 showed greater antioxidant potential in macrophages cells. Moreover, all selected compounds showed improved analgesic activity and 13 b completely abolished the pain response. Additionally, compound 4a showed anticancer activity in tested cell lines HCT116, HT29, and HCA7. Docking results were consistent with COX-1/2 enzyme assay results. In silico studies suggest their high oral bioavailability. The overall findings for compounds (4a,b, 7c, 13 b, and 14c) support their potential role as anti-inflammatory agents.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Hidrazinas/química , Ibuprofeno/química , Indóis/química , Quinazolinonas/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Inibidores de Ciclo-Oxigenase 2/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/farmacologia , Ibuprofeno/síntese química , Ibuprofeno/farmacologia , Indóis/síntese química , Indóis/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Análise Espectral/métodos
3.
Biochim Biophys Acta Gen Subj ; 1865(11): 129990, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34390793

RESUMO

BACKGROUND: Histone lysine-specific demethylase 1 (LSD1) has become a potential anticancer target for the novel drug discovery. Recent reports have shown that SP2509 and its derivatives strongly inhibit LSD1 as allosteric inhibitors. However, the binding mechanism of these allosteric inhibitors in the allosteric site of LSD1 is not known yet. METHODS: The stability and binding mechanism of allosteric inhibitors in the binding site of LSD1 were evaluated by molecular docking, ligand-based pharmacophore, molecular dynamics (MD) simulations, molecular mechanics generalized born surface area (MM/GBSA) analysis, quantum mechanics/molecular mechanics (QM/MM) calculation and Hirshfeld surface analysis. RESULTS: The conformational geometry and the intermolecular interactions of allosteric inhibitors showed high binding affinity towards allosteric site of LSD1 with the neighboring amino acids (Gly358, Cys360, Leu362, Asp375 and Glu379). Meanwhile, MD simulations and MM/GBSA analysis were performed on selected allosteric inhibitors in complex with LSD1 protein, which confirmed the high stability and binding affinity of these inhibitors in the allosteric site of LSD1. CONCLUSION: The simulation results revealed the crucial factors accounting for allosteric inhibitors of LSD1, including different protein-ligand interactions, the positions and conformations of key residues, and the ligands flexibilities. Meanwhile, a halogen bond interaction between chlorine atom of ligand and key residues Trp531 and His532 was recurrent in our analysis confirming its importance. GENERAL SIGNIFICANCE: Overall, our research analyzed in depth the binding modes of allosteric inhibitors with LSD1 and could provide useful information for the design of novel allosteric inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Hidrazinas/farmacologia , Sulfonamidas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Inibidores Enzimáticos/química , Histona Desmetilases/metabolismo , Humanos , Hidrazinas/química , Modelos Moleculares , Estrutura Molecular , Sulfonamidas/química
4.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445782

RESUMO

Spodoptera exigua is a worldwide pest afflicting edible vegetables and has developed varying levels of resistance to insecticides. Methoxyfenozide (MET), an ecdysteroid agonist, is effective against lepidopteran pests such as S. exigua. However, the mechanism of MET to S. exigua remains unclear. In this study, we analyzed the expression patterns of genes related to the ecdysone signaling pathway in transcriptome data treated with sublethal doses of MET and analyzed how expression levels of key genes affect the toxicity of MET on S. exigua. Our results demonstrated that 2639 genes were up-regulated and 2512 genes were down-regulated in S. exigua treated with LC30 of MET. Of these, 15 genes were involved in the ecdysone signaling pathway. qPCR results demonstrated that ecdysone receptor A (EcRA) expression levels significantly increased in S. exigua when treated with different doses of MET, and that the RNAi-mediated silencing of EcRA significantly increased mortality to 55.43% at 72 h when L3 S. exigua larvae were exposed to MET at the LC30 dose. Additionally, knocking down EcRA suppressed the most genes expressed in the ecdysone signaling pathway. The combination of MET and dsEcRA affected the expression of E74 and enhanced the expression of TREA. These results demonstrate that the adverse effects of sublethal MET disturb the ecdysone signaling pathway in S. exigua, and EcRA is closely related to MET toxic effect. This study increases our collective understanding of the mechanisms of MET in insect pests.


Assuntos
Ecdisona/genética , Hidrazinas/farmacologia , Hormônios Juvenis/farmacologia , Interferência de RNA/fisiologia , Transdução de Sinais/efeitos dos fármacos , Spodoptera/efeitos dos fármacos , Transcriptoma/genética , Animais , Perfilação da Expressão Gênica/métodos , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Larva/genética , Receptores de Esteroides/genética , Spodoptera/genética
5.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298987

RESUMO

Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy produced by mutations in the CAPN3 gene. It is a rare disease and there is no cure or treatment for the disease while the pathophysiological mechanism by which the absence of calpain 3 provokes the dystrophy in muscles is not clear. However, key proteins implicated in Wnt and mTOR signaling pathways, which regulate muscle homeostasis, showed a considerable reduction in their expression and in their phosphorylation in LGMDR1 patients' muscles. Finally, the administration of tideglusib and VP0.7, ATP non-competitive inhibitors of glycogen synthase kinase 3ß (GSK-3ß), restore the expression and phosphorylation of these proteins in LGMDR1 cells, opening the possibility of their use as therapeutic options.


Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Sítio Alostérico/efeitos dos fármacos , Antígeno CD56/análise , Calpaína/deficiência , Calpaína/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/química , Humanos , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/enzimologia , Proteínas do Tecido Nervoso/química , Fosforilação , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/fisiologia , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/fisiologia , Tiadiazóis/farmacologia , Tiadiazóis/uso terapêutico , Via de Sinalização Wnt/efeitos dos fármacos
6.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199099

RESUMO

Eltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94.92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP.


Assuntos
Benzoatos/farmacologia , Hidrazinas/farmacologia , Imunomodulação/efeitos dos fármacos , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/metabolismo , Pirazóis/farmacologia , Receptores de Trombopoetina/antagonistas & inibidores , Benzoatos/química , Benzoatos/uso terapêutico , Biomarcadores , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Hidrazinas/química , Hidrazinas/uso terapêutico , Modelos Biológicos , Modelos Moleculares , Terapia de Alvo Molecular/métodos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Receptores de Trombopoetina/química , Receptores de Trombopoetina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
7.
J Enzyme Inhib Med Chem ; 36(1): 1436-1453, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34229558

RESUMO

This study describes the synthesis and vacuole-inducing activity of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carbohydrazide derivatives, including five potent derivatives 12c, 12 g, 12i, 12n, and 12A that exhibit excellent vacuole-inducing activity. Remarkably, 12A effectively induces methuosis in tested cancer cells but not human normal cells. In addition, 12A exhibits high pan-cytotoxicity against different cancer cell lines but is hardly toxic to normal cells. It is found that the 12A-induced vacuoles are derived from macropinosomes but not autophagosomes. The 12A-induced cytoplasmic vacuoles may originate from the endoplasmic reticulum (ER) and be accompanied by ER stress. The MAPK/JNK signalling pathway is involved in the 12A-induced methuotic cell death. Moreover, 12A exhibits significant inhibition of tumour growth in the MDA-MB-231 xenograft mouse model. The excellent potency and selectivity of 12A prompt us to select it as a good lead compound for further development of methuosis inducers and investigation of the molecular and cellular mechanisms underlying methuosis.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Hidrazinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
J Enzyme Inhib Med Chem ; 36(1): 1651-1658, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34294008

RESUMO

A set of 1,3,4-thiadiazole-2-carboxamides bearing a substituted biphenyl in the amide portion was synthesised and tested for agonistic activity towards free fatty acid receptor 1 (FFA1). The observed activity trends were impossible to rationalised based solely on the docking energy scores of Glide SP. On the contrary, when the phospholipid cell membrane bilayer was reconstructed around FFA1, it became apparent that inactive compounds displayed significant strained contacts with the membrane while for active compounds the strain was noticeably lower. These findings justify using the improved docking protocol for modelling GPCR-ligand interactions which uses the crystal structure of the receptor and a reconstructed portion of a cell membrane.


Assuntos
Hidrazinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Bibliotecas de Moléculas Pequenas/farmacologia , Membrana Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Ligantes , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 222: 113577, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34087544

RESUMO

One of the major causes of neurodegeneration in the pathogenesis of Alzheimer's disease is the accumulation of cytotoxic amyloid species within the intercellular compartments of the brain. The efficacy of the anti-proteotoxic mechanism based on the molecular chaperones Hsp70 and Hsp90 in numerous types of neurons is often low, while its pharmacological enhancement has been shown to ameliorate the physiological and cognitive functions of the brain. Suggesting that the chemicals able to induce heat shock protein synthesis and therefore rescue neural cells from cytotoxicity associated with amyloid, we have synthesized a group of pyrrolyl- and indolylazines that cause the accumulation of heat shock proteins, using a novel method of photocatalysis that is employed in green chemistry. The selected compounds were tested in a cell model of Alzheimer's disease and demonstrated a pronounced neuroprotective effect. These substances increased the survival of neurons, blocked the activation of ß-galactosidase, and prevented apoptosis in neurons cultured in the presence of ß-amyloid.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Hidrazinas/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pirróis/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Apoptose/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Estrutura Molecular , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
10.
Eur J Med Chem ; 221: 113567, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34082224

RESUMO

Neuraminidase (NA) inhibitors play a prime role in treating influenza. However, a variety of viruses containing mutant NAs have developed severe drug resistance towards NA inhibitors, so it is of crucial significance to solve this problem. Encouraged by urea-containing compound 12 disclosed by our lab, we designed a series of oseltamivir derivatives bearing hydrazide fragment for targeting the 150 cavity. Among the synthesized compounds, compound 17a showed 8.77-fold, 4.12-fold, 203-fold and 6.23-fold more potent activity than oseltamivir carboxylate against NAs from H5N1, H1N1, H5N1-H274Y, H1N1-H274Y, respectively. Meanwhile, the best compound 17a exhibited satisfactory metabolic stability in vitro. This study offers an important reference for the structural optimization of oseltamivir aiming at potent inhibition against H274Y mutant of NAs.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Proteínas Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Vírus da Influenza A/enzimologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mutação , Neuraminidase/genética , Neuraminidase/metabolismo , Oseltamivir/síntese química , Oseltamivir/química , Relação Estrutura-Atividade , Proteínas Virais/genética , Proteínas Virais/metabolismo
11.
Antiviral Res ; 192: 105115, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34157321

RESUMO

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the recent global pandemic. The nuclear export protein (XPO1) has a direct role in the export of SARS-CoV proteins including ORF3b, ORF9b, and nucleocapsid. Inhibition of XPO1 induces anti-inflammatory, anti-viral, and antioxidant pathways. Selinexor is an FDA-approved XPO1 inhibitor. Through bioinformatics analysis, we predicted nuclear export sequences in the ACE-2 protein and confirmed by in vitro testing that inhibition of XPO1 with selinexor induces nuclear localization of ACE-2. Administration of selinexor inhibited viral infection prophylactically as well as therapeutically in vitro. In a ferret model of COVID-19, selinexor treatment reduced viral load in the lungs and protected against tissue damage in the nasal turbinates and lungs in vivo. Our studies demonstrated that selinexor downregulated the pro-inflammatory cytokines IL-1ß, IL-6, IL-10, IFN-γ, TNF-α, and GMCSF, commonly associated with the cytokine storm observed in COVID-19 patients. Our findings indicate that nuclear export is critical for SARS-CoV-2 infection and for COVID-19 pathology and suggest that inhibition of XPO1 by selinexor could be a viable anti-viral treatment option.


Assuntos
COVID-19/tratamento farmacológico , Hidrazinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Triazóis/farmacologia , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/farmacologia , COVID-19/virologia , Chlorocebus aethiops , Citocinas , Furões , Humanos , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/virologia , SARS-CoV-2/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Células Vero , Replicação Viral
12.
Acta Biochim Biophys Sin (Shanghai) ; 53(8): 1098-1105, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34169322

RESUMO

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling promotes tumorigenesis and cancer progression. STAT3 participates in the essential processes of cell proliferation, survival, and differentiation in many types of tumors. In the present study, SP2509 was identified as a potent inhibitor of the JAK/STAT3 signaling pathway by high-throughput drug screening based on a STAT3-driven luciferase expression system. Our results indicated that SP2509 inhibits constitutive STAT3 activation and the expression of STAT3-driven downstream genes. Bcl-xL, c-Myc, and Cyclin D1 were downregulated after treatment with SP2509. In addition, SP2509 specifically inhibits JAK activity, which could cause cell cycle arrest, inhibit cell growth, and induce apoptosis of various cancer cells. These results confirmed that SP2509 inhibits tumor progression by suppressing the expression of JAK/STAT3 signaling and STAT3-related downstream genes. Moreover, we demonstrated that SP2509 inhibits tumor growth in vivo and induces cell death in vitro. SP2509-mediated inhibition of STAT3 phosphorylation is dependent on its original target lysine-specific demethylase 1 in cancer cells. In summary, our results indicate that SP2509 is a novel inhibitor of JAK/STAT3 signaling.


Assuntos
Antineoplásicos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Hidrazinas/farmacologia , Proteínas de Neoplasias , Neoplasias/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Células A549 , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Janus Quinases/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética
13.
Proteins ; 89(11): 1425-1441, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34169568

RESUMO

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro ), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, Food and Drug Administration (FDA)-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. Fourteen best molecule hits for the active site of Mpro are determined. Six of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind ) values. ∆Gbind values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and - 42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin, and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS-CoV-2 infections.


Assuntos
Antivirais/metabolismo , Benzofuranos/química , Proteases 3C de Coronavírus/metabolismo , Reposicionamento de Medicamentos/métodos , Imidazóis/química , Sítio Alostérico , Antivirais/química , Antivirais/farmacologia , Benzofuranos/metabolismo , Benzofuranos/farmacologia , Sítios de Ligação , Bromocriptina/química , Bromocriptina/metabolismo , Bromocriptina/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Diosmina/química , Diosmina/metabolismo , Hidrazinas/química , Hidrazinas/metabolismo , Hidrazinas/farmacologia , Imidazóis/metabolismo , Imidazóis/farmacologia , Ivermectina/química , Ivermectina/metabolismo , Ivermectina/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Triazóis/química , Triazóis/metabolismo , Triazóis/farmacologia , Estados Unidos , United States Food and Drug Administration
14.
Elife ; 102021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34059198

RESUMO

Thrombocytopenic disorders have been treated with the Thrombopoietin-receptor agonist Eltrombopag. Patients with the same apparent form of thrombocytopenia may respond differently to the treatment. We describe a miniaturized bone marrow tissue model that provides a screening bioreactor for personalized, pre-treatment response prediction to Eltrombopag for individual patients. Using silk fibroin, a 3D bone marrow niche was developed that reproduces platelet biogenesis. Hematopoietic progenitors were isolated from a small amount of peripheral blood of patients with mutations in ANKRD26 and MYH9 genes, who had previously received Eltrombopag. The ex vivo response was strongly correlated with the in vivo platelet response. Induced Pluripotent Stem Cells (iPSCs) from one patient with mutated MYH9 differentiated into functional megakaryocytes that responded to Eltrombopag. Combining patient-derived cells and iPSCs with the 3D bone marrow model technology allows having a reproducible system for studying drug mechanisms and for individualized, pre-treatment selection of effective therapy in Inherited Thrombocytopenias.


Assuntos
Benzoatos/farmacologia , Plaquetas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hidrazinas/farmacologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Megacariócitos/efeitos dos fármacos , Pirazóis/farmacologia , Receptores de Trombopoetina/agonistas , Nicho de Células-Tronco , Trombocitopenia/tratamento farmacológico , Trombopoese/efeitos dos fármacos , Adulto , Idoso , Reatores Biológicos , Plaquetas/metabolismo , Técnicas de Cultura de Células , Células Cultivadas , Feminino , Fibroínas/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Megacariócitos/metabolismo , Pessoa de Meia-Idade , Miniaturização , Mutação , Cadeias Pesadas de Miosina/genética , Receptores de Trombopoetina/metabolismo , Trombocitopenia/sangue , Trombocitopenia/genética , Adulto Jovem
15.
Cells ; 10(4)2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810313

RESUMO

Diamond Blackfan Anemia (DBA) is a congenital macrocytic anemia associated with ribosomal protein haploinsufficiency. Ribosomal dysfunction delays globin synthesis, resulting in excess toxic free heme in erythroid progenitors, early differentiation arrest, and pure red cell aplasia. In this study, DBA induced pluripotent stem cell (iPSC) lines were generated from blood mononuclear cells of DBA patients with inactivating mutations in RPS19 and subjected to hematopoietic differentiation to model disease phenotypes. In vitro differentiated hematopoietic cells were used to investigate whether eltrombopag, an FDA-approved mimetic of thrombopoietin with robust intracellular iron chelating properties, could rescue erythropoiesis in DBA by restricting the labile iron pool (LIP) derived from excessive free heme. DBA iPSCs exhibited RPS19 haploinsufficiency, reduction in the 40S/60S ribosomal subunit ratio and early erythroid differentiation arrest in the absence of eltrombopag, compared to control isogenic iPSCs established by CRISPR/Cas9-mediated correction of the RPS19 point mutation. Notably, differentiation of DBA iPSCs in the presence of eltrombopag markedly improved erythroid maturation. Consistent with a molecular mechanism based on intracellular iron chelation, we observed that deferasirox, a clinically licensed iron chelator able to permeate into cells, also enhanced erythropoiesis in our DBA iPSC model. In contrast, erythroid maturation did not improve substantially in DBA iPSC differentiation cultures supplemented with deferoxamine, a clinically available iron chelator that poorly accesses LIP within cellular compartments. These findings identify eltrombopag as a promising new therapeutic to improve anemia in DBA.


Assuntos
Anemia de Diamond-Blackfan/tratamento farmacológico , Anemia de Diamond-Blackfan/patologia , Benzoatos/uso terapêutico , Diferenciação Celular , Células Eritroides/patologia , Hidrazinas/uso terapêutico , Células-Tronco Pluripotentes Induzidas/patologia , Modelos Biológicos , Pirazóis/uso terapêutico , Anemia de Diamond-Blackfan/genética , Animais , Sequência de Bases , Benzoatos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Células Eritroides/efeitos dos fármacos , Eritropoese , Humanos , Hidrazinas/farmacologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Espaço Intracelular/metabolismo , Ferro/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação/genética , Pirazóis/farmacologia
16.
Clin Appl Thromb Hemost ; 27: 10760296211005555, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33874785

RESUMO

Eltrombopag is an orally administered, non-peptide, thrombopoietin receptor agonist which initiates thrombopoietin signaling and stimulates the production of normally functioning platelet. We aimed to do a systematic review and meta-analysis of currently available published data to verify whether eltrombopag treatment in patients with chronic immune-mediated thrombocytopenia can prolong survival. We searched for published, randomized, controlled trials in PubMed, Cochrane and Scopus databases using the following search strategy ("Eltrombopag" OR "Benzoates" OR "Hydrazines") AND ("Idiopathic Thrombocytopenic Purpura" OR "immune thrombocytopenia" OR "Idiopathic Thrombocytopenic Purpuras" OR "Immune Thrombocytopenia" OR "Autoimmune Thrombocytopenia" OR "Werlhof"). The pooled relative risk (RR) showed that eltrombopag group has significantly higher overall platelet response than placebo group (MD = 3.42, 95% CI [2.51, 4.65], P > .0001); pooled results were homogenous (P = .27, I2 = 22%). The pooled relative risk showed that eltrombopag group has lower incidence of any bleeding than placebo group (MD = 0.65, 95% CI [0.48, 0.87], P = .003); pooled results were heterogenous (P = .001, I2 = 75%) and the detected heterogeneity was best resolved after excluding Bussel et al (P = .10). Homogeneous results were still favored eltrombopag group (MD = 0.75, 95% CI [0.60, 0.93], P = .008).


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Benzoatos/farmacologia , Doença Crônica , Humanos , Hidrazinas/farmacologia , Pirazóis/farmacologia
17.
Eur J Med Chem ; 220: 113431, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33915371

RESUMO

Duchenne muscular dystrophy is a fatal disease with no cure, caused by lack of the cytoskeletal protein dystrophin. Upregulation of utrophin, a dystrophin paralogue, offers a potential therapy independent of mutation type. The failure of first-in-class utrophin modulator ezutromid/SMT C1100 in Phase II clinical trials necessitates development of compounds with better efficacy, physicochemical and ADME properties and/or complementary mechanisms. We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter. We further demonstrate through target deconvolution studies, including expression analysis and chemical proteomics, that this compound series operates via a novel mechanism of action, distinct from that of ezutromid.


Assuntos
Descoberta de Drogas , Hidrazinas/farmacologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Pirimidinas/farmacologia , Utrofina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Estrutura Molecular , Distrofia Muscular de Duchenne/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade
18.
J Hematol Oncol ; 14(1): 59, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849608

RESUMO

Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40 mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80 mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100 mg) with once weekly subcutaneous bortezomib (1.3 mg/m2) and 40 mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80 mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT.Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Hidrazinas/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Triazóis/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bortezomib/farmacologia , Dexametasona/farmacologia , Feminino , Humanos , Hidrazinas/farmacologia , Masculino , Mieloma Múltiplo/patologia , Triazóis/farmacologia
19.
Eur J Med Chem ; 219: 113424, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-33862514

RESUMO

Triple negative breast cancer (TNBC) has a worse prognosis than other types of breast cancer due to its special biological behavior and clinicopathological characteristics. TNBC cell proliferation and progression to metastasis can be suppressed by inducing cytostatic autophagy. mTOR is closely related to autophagy and is involved in protein synthesis, nutrient metabolism and activating mTOR promotes tumor growth and metastasis. In this paper, we adopted the strategy of structure simplification, aimed to look for novel small-molecule inhibitors of mTOR by pharmacophore-based virtual screening and biological activity determination. We found a lead compound with 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide for rational drug design and structural modification, then studied its structure-activity relationship. After that, compound 7c with the best TNBC cells inhibitory activities and superior mTOR enzyme inhibitory activity was obtained. In addition, we found that compound 7c could induce autophagic cell death and apoptosis in MDA-MB-231 and MDA-MB-468 cell lines. In conclusion, these findings provide new clues for our 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives, which are expected to become drug candidates for the treatment of TNBC in the future.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Hidrazinas/química , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/metabolismo , Hidrazinas/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
20.
Int J Biol Macromol ; 182: 534-544, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33839183

RESUMO

Urease is potential target for various human's health complications, such as peptic ulcer, gastric cancer and kidney stone formation. The present study was based on synthesis of new hybrid pharmacophore N-substituted hydrazine-carbothioamides as potential urease inhibitors. Presented method gave excellent yield in range of 85-95% for hydrazine-carbothioamides derivatives (3a-s) after reaction of mono- and disubstituted hydrazides (1a-k) and substituted isothiocyanates (2a-d). All newly derivatives were characterized by advanced spectroscopic techniques (FTIR, 1HNMR, 13CNMR, EMS) and were assessed for their urease inhibition potential. All analogs except for 3k, 3l and 3m demonstrated strong inhibitory potential for urease with IC50 values of 8.45 ± 0.14 to 25.72 ± 0.23 µM as compared to standard thiourea (IC50 21.26 ± 0.35 µM). The structure-activity relationship and mode of interaction was established by molecular docking studies. It was revealed that the N-substituted hydrazine-carbothioamides interacted with nickel atoms present in the active site of urease and supported the correlations with the experimental findings. Therefore, the afforded hydrazine-carbothioamides derivatives are interesting hits for urease inhibition studies with future prospects of modification and optimization.


Assuntos
Inibidores Enzimáticos/química , Hidrazinas/química , Relação Quantitativa Estrutura-Atividade , Tioamidas/química , Urease/antagonistas & inibidores , Sítios de Ligação , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Simulação de Acoplamento Molecular , Ligação Proteica , Tioamidas/farmacologia , Urease/química , Urease/metabolismo
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