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1.
Science ; 373(6554): 541-547, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34326236

RESUMO

Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities-rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Lipidoses/induzido quimicamente , Fosfolipídeos/metabolismo , SARS-CoV-2/efeitos dos fármacos , Células A549 , Animais , Antivirais/química , Antivirais/uso terapêutico , Antivirais/toxicidade , COVID-19/virologia , Cátions , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , SARS-CoV-2/fisiologia , Tensoativos/química , Tensoativos/farmacologia , Tensoativos/toxicidade , Células Vero , Replicação Viral/efeitos dos fármacos
2.
J Med Chem ; 63(21): 12542-12573, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32930584

RESUMO

FGF19 signaling through the FGFR4/ß-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.


Assuntos
Piperazinas/química , Inibidores de Proteínas Quinases/química , Piridinas/química , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisteína/química , Cães , Desenho de Fármacos , Meia-Vida , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Piperazinas/metabolismo , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Mol Cancer Ther ; 18(12): 2194-2206, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31409633

RESUMO

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through the FGF19/FGFR4 axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3, and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic/pharmacodynamics/efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC90 value. FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a phase I/II study is currently ongoing in HCC and other solid malignancies.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Transdução de Sinais
4.
Toxicol Sci ; 163(1): 265-278, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29432567

RESUMO

The FGF19- fibroblast growth factor receptor (FGFR4)-ßKlotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1, elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one, increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and coadministration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid and taurodeoxycholic acid, the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels.


Assuntos
Alanina Transaminase/sangue , Ácidos e Sais Biliares/sangue , Resina de Colestiramina/farmacologia , Fígado/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Alanina Transaminase/biossíntese , Animais , Ácidos e Sais Biliares/biossíntese , Cães , Relação Dose-Resposta a Droga , Feminino , Fígado/enzimologia , Masculino , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/sangue , Piridinas/farmacologia , Testes de Toxicidade , Toxicocinética
5.
Toxicol Appl Pharmacol ; 309: 55-62, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27576608

RESUMO

AUY922, a heat shock protein 90 inhibitor is associated with ocular adverse events (AEs). To provide a better understanding of ocular AEs in patients, 4 investigative studies were performed in a step-wise approach to assess retinal structure and function in pigmented (Brown Norway) and albino (Wistar) rats. In rats administered 30mg/kg of AUY922, the AUC0-24h and Cmax are comparable to that in patients at 70mg/m(2). AUY922 at ≥30mg/kg was poorly tolerated by rats with morbidity or mortality generally after the third weekly treatment. Electroretinography (ERG) changes were observed at doses ≥30mg/kg. The ERG changes were dose dependent, consistent with an effect on the photoreceptors, and fully reversible. The ERG effects could not be minimized by decreasing the Cmax while maintaining AUC. Histopathological changes were seen mainly when rats were administered AUY922 at 100mg/kg. The 2-hour infusion of AUY922 at 100mg/kg caused disorganization of the outer segment photoreceptor morphology in male Brown Norway rats; the severity of the disorganization increased with the number of administrations, but was reversible during a 4-week posttreatment period. There was no major difference in ocular response between Brown Norway and Wistar rats. No changes in serum iron levels, and no changes in rhodopsin, PDE6α, ß-transducin concentrations, or retinal pigment epithelium-specific protein RPE65 expression were observed after single and multiple infusions of AUY922 at 100mg/kg compared to vehicle-treated controls. AUY922 retinal toxicity in rats recapitulates and further characterizes that reported in patients and is shown to be reversible, while a precise molecular mechanism for the effect was not determined.


Assuntos
Olho/efeitos dos fármacos , Animais , Eletrorretinografia , Olho/fisiopatologia , Isoxazóis/toxicidade , Ratos , Ratos Wistar , Resorcinóis/toxicidade
6.
Clin Res Hepatol Gastroenterol ; 40(3): 257-266, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26874804

RESUMO

Bile acid research has gained great momentum since the role of bile acids as key signaling molecules in the enterohepatic circulation was discovered. Their physiological function in regulating their own homeostasis, as well as energy and lipid metabolism make them interesting targets for the pharmaceutical industry in the context of diseases such as bile acid induced diarrhea, bile acid induced cholestasis or nonalcoholic steatohepatitis. Changes in bile acid homeostasis are also linked to various types of drug-induced liver injury (DILI). However, the key question whether bile acids are surrogate markers for monitoring DILI or key pathogenic players in the onset and progression of DILI is under intense investigation. The purpose of this review is to summarize the different facets of bile acids in the context of normal physiology, hereditary defects of bile acid transport and DILI.


Assuntos
Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ductos Biliares/citologia , Transporte Biológico/fisiologia , Biomarcadores/metabolismo , Colestase Intra-Hepática/induzido quimicamente , Colestase Intra-Hepática/fisiopatologia , Circulação Êntero-Hepática/fisiologia , Homeostase , Humanos
7.
J AOAC Int ; 95(5): 1487-94, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23175984

RESUMO

A rapid, sensitive, and selective method for the quantification of vitamin D3 (cholecalciferol) in solid and liquid food, feed, and tablets based on HPLC/MS/MS has been developed and validated. The sample preparation procedure consists of a quick and robust alkaline saponification and liquid-liquid extraction, followed by direct injection of the organic extract into the HPLC/MS/MS system for analysis without any further concentration, reconstitution, or prepurification steps. The reduction in sample preparation time was achieved by applying a heart-cutting, two-dimensional chromatography technique prior to positive electrospray ionization selected reaction monitoring MS analysis. Total vitamin D3 (sum of previtamin D3 and vitamin D3) was quantified using an isotopically labeled internal standard. The ionization efficiency of previtamin D3 and vitamin D3 in the positive electrospray ionization mode was found to be very similar. The validation experiments included four feed matrixes, three types of tablets, and 12 food matrixes. The obtained recoveries were between 96.1 and 105.3%, and intermediate precision ranged from 1.32 to 15.6% RSD, with HorRat values between 0.07 and 0.65. For all samples, extraction efficiencies were above 95.8%. Analysis of two certified reference materials (SRM 1849 and BCR-122) gave accuracies of 102.4 and 99.8%, respectively.


Assuntos
Colecalciferol/química , Cromatografia Líquida de Alta Pressão/métodos , Análise de Alimentos/métodos , Preparações Farmacêuticas/análise , Espectrometria de Massas em Tandem/métodos , Ração Animal , Estrutura Molecular , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray
8.
J Am Chem Soc ; 131(10): 3481-3, 2009 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-19275258

RESUMO

Chorismate is an important and central metabolite branching off to the biosyntheses of aromatic amino acids and p-aminobenzoic acid (pABA), a component of the vitamin folic acid. Here we report on a novel variation of a unified catalytic mechanism in Bacillus subtilis pABA biosynthesis that includes the formation of a new intermediate, 2-amino-2-deoxyisochorismate (ADIC), thus significantly differing from the mechanism in Escherichia coli. In B. subtilis, chorismate is converted to ADIC, which is catalyzed by aminodeoxychorismate synthase (ADCS). In a second step, ADIC is converted to aminodeoxychorismate (ADC) by addition of ammonia to C4, also catalyzed by ADCS. The third step is the aminodeoxychorismate lyase-catalyzed elimination of pyruvate from ADC. To our knowledge, B. subtilis aminodeoxychorismate synthase is the first enzyme exhibiting ADIC synthase activity in primary metabolism. We further provide evidence that pABA biosynthesis via ADIC might be a common mechanism for several other microorganisms.


Assuntos
Aminobenzoatos/metabolismo , Bacillus subtilis/química , Ácidos Cicloexanocarboxílicos/química , Catálise , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas
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