Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Cancer Ther ; 18(5): 909-919, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30872381

RESUMO

Barasertib (AZD1152), a pro-drug of the highly potent and selective Aurora B kinase inhibitor AZD2811, showed promising clinical activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients administered as a 4-day infusion. To improve potential therapeutic benefit of Aurora B kinase inhibition, a nanoparticle formulation of AZD2811 has been developed to address limitations of repeated intravenous infusion. One of the challenges with the use of nanoparticles for chronic treatment of tumors is optimizing dose and schedule required to enable repeat administration to sustain tumor growth inhibition. AZD2811 gives potent cell growth inhibition across a range of DLBCL cells lines in vitro In vivo, repeat administration of the AZD2811 nanoparticle gave antitumor activity at half the dose intensity of AZD1152. Compared with AZD1152, a single dose of AZD2811 nanoparticle gave less reduction in pHH3, but increased apoptosis and reduction of cells in G1 and G2-M, albeit at later time points, suggesting that duration and depth of target inhibition influence the nature of the tumor cell response to drug. Further exploration of the influence of dose and schedule on efficacy revealed that AZD2811 nanoparticle can be used flexibly with repeat administration of 25 mg/kg administered up to 7 days apart being sufficient to maintain equivalent tumor control. Timing of repeat administration could be varied with 50 mg/kg every 2 weeks controlling tumor control as effectively as 25 mg/kg every week. AZD2811 nanoparticle can be administered with very different doses and schedules to inhibit DLBCL tumor growth, although maximal tumor growth inhibition was achieved with the highest dose intensities.


Assuntos
Acetanilidas/farmacologia , Aurora Quinase B/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Acetanilidas/química , Animais , Aurora Quinase B/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Nanopartículas/química , Inibidores de Proteínas Quinases/química , Quinazolinas/química , Ensaios Antitumorais Modelo de Xenoenxerto
2.
SLAS Discov ; 23(1): 11-22, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28945981

RESUMO

A high-throughput screen (HTS) of human 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) resulted in several series of compounds with the potential for further optimization. Informatics was used to identify active chemotypes with lead-like profiles and remove compounds that commonly occurred as actives in other HTS screens. The activities were confirmed with IC50 measurements from two orthogonal assay technologies, and further analysis of the Hill slopes and comparison of the ratio of IC50 values at 10 times the enzyme concentration were used to identify artifact compounds. Several series of compounds were rejected as they had both high slopes and poor ratios. A small number of compounds representing the different leading series were assessed using isothermal titration calorimetry, and the X-ray crystal structure of the complex with PFKFB3 was solved. The orthogonal assay technology and isothermal calorimetry were demonstrated to be unreliable in identifying false-positive compounds in this case. Presented here is the discovery of the dihydropyrrolopyrimidinone series of compounds as active and novel inhibitors of PFKFB3, shown by X-ray crystallography to bind to the adenosine triphosphate site. The crystal structures of this series also reveal it is possible to flip the binding mode of the compounds, and the alternative orientation can be driven by a sigma-hole interaction between an aromatic chlorine atom and a backbone carbonyl oxygen. These novel inhibitors will enable studies to explore the role of PFKFB3 in driving the glycolytic phenotype of tumors.


Assuntos
Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Fosfofrutoquinase-2/antagonistas & inibidores , Antineoplásicos/química , Calorimetria/métodos , Inibidores Enzimáticos/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fosfofrutoquinase-2/química , Fosfofrutoquinase-2/genética , Fosfofrutoquinase-2/metabolismo , Relação Quantitativa Estrutura-Atividade , Bibliotecas de Moléculas Pequenas , Fluxo de Trabalho
3.
Oncotarget ; 8(41): 69219-69236, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-29050199

RESUMO

Tumors frequently display a glycolytic phenotype with increased flux through glycolysis and concomitant synthesis of lactate. To maintain glycolytic flux and prevent intracellular acidification, tumors efflux lactate via lactate transporters (MCT1-4). Inhibitors of lactate transport have the potential to inhibit glycolysis and tumor growth. We developed a small molecule inhibitor of MCT1 (AZD3965) and assessed its activity across a panel of cell lines. We explored its antitumor activity as monotherapy and in combination with doxorubicin or rituximab. AZD3965 is a potent inhibitor of MCT1 with activity against MCT2 but selectivity over MCT3 and MCT4. In vitro, AZD3965 inhibited the growth of a range of cell lines especially haematological cells. Inhibition of MCT1 by AZD3965 inhibited lactate efflux and resulted in accumulation of glycolytic intermediates. In vivo, AZD3965 caused lactate accumulation in the Raji Burkitt's lymphoma model and significant tumor growth inhibition. Moreover, AZD3965 can be combined with doxorubicin or rituximab, components of the R-CHOP standard-of-care in DLBCL and Burkitt's lymphoma. Finally, combining lactate transport inhibition by AZD3965 with GLS1 inhibition in vitro, enhanced cell growth inhibition and cell death compared to monotherapy treatment. The ability to combine AZD3965 with novel, and standard-of-care inhibitors offers novel combination opportunities in haematological cancers.

4.
Mol Cancer Ther ; 16(6): 1031-1040, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28292940

RESUMO

Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly acute myeloid leukemia (AML) patients. However, clinical utility was limited by the requirement for a 7-day infusion. Here we assessed the potential of a nanoparticle formulation of the selective Aurora kinase B inhibitor AZD2811 (formerly known as AZD1152-hQPA) in preclinical models of AML. When administered to HL-60 tumor xenografts at a single dose between 25 and 98.7 mg/kg, AZD2811 nanoparticle treatment delivered profound inhibition of tumor growth, exceeding the activity of AZD1152. The improved antitumor activity was associated with increased phospho-histone H3 inhibition, polyploidy, and tumor cell apoptosis. Moreover, AZD2811 nanoparticles increased antitumor activity when combined with cytosine arabinoside. By modifying dose of AZD2811 nanoparticle, therapeutic benefit in a range of preclinical models was further optimized. At high-dose, antitumor activity was seen in a range of models including the MOLM-13 disseminated model. At these higher doses, a transient reduction in bone marrow cellularity was observed demonstrating the potential for the formulation to target residual disease in the bone marrow, a key consideration when treating AML. Collectively, these data establish that AZD2811 nanoparticles have activity in preclinical models of AML. Targeting Aurora B kinase with AZD2811 nanoparticles is a novel approach to deliver a cell-cycle inhibitor in AML, and have potential to improve on the clinical activity seen with cell-cycle agents in this disease. Mol Cancer Ther; 16(6); 1031-40. ©2017 AACR.


Assuntos
Antineoplásicos/administração & dosagem , Aurora Quinase B/antagonistas & inibidores , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Nanopartículas , Organofosfatos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinas/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/patologia , Linhagem Celular Tumoral , Citarabina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Células HL-60 , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Camundongos , Organofosfatos/farmacocinética , Poliploidia , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/farmacocinética , Ratos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Med Chem ; 58(8): 3611-25, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25849762

RESUMO

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.


Assuntos
Desenho de Fármacos , Fosfofrutoquinase-2/antagonistas & inibidores , Fosfofrutoquinase-2/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Linhagem Celular , Humanos , Masculino , Camundongos , Modelos Moleculares , Fosfofrutoquinase-2/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Ratos Wistar , Relação Estrutura-Atividade
6.
Antimicrob Agents Chemother ; 54(10): 4416-23, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20643901

RESUMO

A mariner transposon bank was used to identify loci that contribute to the innate resistance of Listeria monocytogenes to the lantibiotic nisin. In addition to highlighting the importance of a number of loci previously associated with nisin resistance (mprF, virRS, and telA), a nisin-sensitive phenotype was associated with the disruption of anrB (lmo2115), a gene encoding the permease component of an ABC transporter. The contribution of anrB to nisin resistance was confirmed by the creation of nonpolar deletion mutants. The loss of this putative multidrug resistance transporter also greatly enhanced sensitivity to bacitracin, gallidermin, and a selection of ß-lactam antibiotics. A comparison of the relative antimicrobial sensitivities of a number of mutants established the ΔanrB strain as being one of the most bacitracin-sensitive L. monocytogenes strains identified to date.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Antibacterianos/farmacologia , Bacitracina/farmacologia , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/metabolismo , Nisina/farmacologia , Resistência beta-Lactâmica/genética , Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Listeria monocytogenes/genética
7.
J Fam Psychol ; 23(2): 119-29, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19364207

RESUMO

The transportability of Multisystemic Therapy (MST) for the treatment of juvenile offenders in a community-based context was examined in the current study. Results of this New Zealand study showed that significant pre- to posttreatment improvements occurred on most indicators of ultimate (i.e., offending behavior) and instrumental (i.e., youth compliance, family relations) treatment outcomes. Reductions in offending frequency and severity continued to improve across the 6- and 12-month follow-up intervals. In comparison to benchmarked studies, the current study demonstrated a more successful treatment completion rate. Additionally, overall treatment effect sizes were found to be clinically equivalent with the results of previous MST outcome studies with juvenile offenders and significantly greater than the effect sizes found in the control conditions. The findings of this evaluation add to the growing body of evidence that supports MST as an effective treatment for antisocial youth.


Assuntos
Benchmarking/métodos , Transtorno da Conduta/terapia , Terapia Familiar/métodos , Delinquência Juvenil/reabilitação , Adolescente , Comportamento do Adolescente , Benchmarking/estatística & dados numéricos , Criança , Relações Familiares , Terapia Familiar/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Controle Interno-Externo , Delinquência Juvenil/prevenção & controle , Delinquência Juvenil/estatística & dados numéricos , Masculino , Nova Zelândia , Satisfação do Paciente , Avaliação de Programas e Projetos de Saúde/métodos , Índice de Gravidade de Doença , Resultado do Tratamento
8.
J Fam Psychol ; 18(3): 411-9, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15382965

RESUMO

Multisystemic treatment (MST) is a family- and home-based therapeutic approach that has been found to be effective in treating antisocial youths and that has recently been applied to youths with serious emotional disturbances. In light of the increasing dissemination of MST, this review examines the effectiveness of MST by quantifying and summarizing the magnitude of effects (treatment outcomes) across all eligible MST outcome studies. Included in a meta-analysis were 7 primary outcome studies and 4 secondary studies involving a total of 708 participants. Results indicated that across different presenting problems and samples, the average effect of MST was d = .55; following treatment, youths and their families treated with MST were functioning better than 70% of youths and families treated alternatively. Results also showed that the average effect of MST was larger in studies involving graduate student therapists (i.e., efficacy studies; d = .81) than in studies with therapists from the community (i.e., effectiveness studies; d = .26). In addition, MST demonstrated larger effects on measures of family relations than on measures of individual adjustment or peer relations.


Assuntos
Centros Comunitários de Saúde Mental , Terapia Familiar , Hospitalização , Delinquência Juvenil/reabilitação , Transtornos Mentais/reabilitação , Centros de Tratamento de Abuso de Substâncias , Transtornos Relacionados ao Uso de Substâncias/reabilitação , Adolescente , Transtorno da Personalidade Antissocial/psicologia , Transtorno da Personalidade Antissocial/reabilitação , Criança , Maus-Tratos Infantis/psicologia , Maus-Tratos Infantis/reabilitação , Terapia Combinada , Hospitais Psiquiátricos , Humanos , Delinquência Juvenil/psicologia , Transtornos Mentais/psicologia , Avaliação de Resultados em Cuidados de Saúde , Transtornos Relacionados ao Uso de Substâncias/psicologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...