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1.
Nat Nanotechnol ; 18(11): 1351-1363, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37443252

RESUMO

Intravenously administered cyclic dinucleotides and other STING agonists are hampered by low cellular uptake and poor circulatory half-life. Here we report the covalent conjugation of cyclic dinucleotides to poly(ß-amino ester) nanoparticles through a cathepsin-sensitive linker. This is shown to increase stability and loading, thereby expanding the therapeutic window in multiple syngeneic tumour models, enabling the study of how the long-term fate of the nanoparticles affects the immune response. In a melanoma mouse model, primary tumour clearance depends on the STING signalling by host cells-rather than cancer cells-and immune memory depends on the spleen. The cancer cells act as a depot for the nanoparticles, releasing them over time to activate nearby immune cells to control tumour growth. Collectively, this work highlights the importance of nanoparticle structure and nano-biointeractions in controlling immunotherapy efficacy.


Assuntos
Melanoma , Nanopartículas , Neoplasias , Animais , Camundongos , Polímeros/farmacologia , Neoplasias/tratamento farmacológico , Transdução de Sinais , Nanopartículas/uso terapêutico , Nanopartículas/química
2.
J Med Chem ; 64(10): 6902-6923, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34000802

RESUMO

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.


Assuntos
Proteínas de Membrana/agonistas , Nucleotídeos Cíclicos/química , Pirimidinas/química , Administração Intravenosa , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Meia-Vida , Humanos , Imunoterapia , Proteínas de Membrana/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Neoplasias/patologia , Neoplasias/terapia , Nucleotídeos Cíclicos/metabolismo , Nucleotídeos Cíclicos/uso terapêutico , Fosfatos/química , Ratos , Relação Estrutura-Atividade , Transplante Heterólogo
3.
J Med Chem ; 64(5): 2501-2520, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33631934

RESUMO

SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Ácidos Sulfônicos/uso terapêutico , Sumoilação/efeitos dos fármacos , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Camundongos , Estrutura Molecular , Ligação Proteica , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/metabolismo , Enzimas Ativadoras de Ubiquitina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Bioorg Med Chem ; 28(19): 115681, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32912429

RESUMO

Autophagy is postulated to be required by cancer cells to survive periods of metabolic and/or hypoxic stress. ATG7 is the E1 enzyme that is required for activation of Ubl conjugation pathways involved in autophagosome formation. This article describes the design and optimization of pyrazolopyrimidine sulfamate compounds as potent and selective inhibitors of ATG7. Cellular levels of the autophagy markers, LC3B and NBR1, are regulated following treatment with these compounds.


Assuntos
Proteína 7 Relacionada à Autofagia/antagonistas & inibidores , Descoberta de Drogas , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ácidos Sulfônicos/farmacologia , Autofagia/efeitos dos fármacos , Proteína 7 Relacionada à Autofagia/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/química
5.
Bioanalysis ; 8(9): 871-80, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27072051

RESUMO

The desire for serial microsampling in mice has led to extensive research in this field within the pharmaceutical industry. The ability to profile a compound's in vivo properties with less material and fewer mice has obvious advantages. A new device and workflow was developed at the Takeda Oncology site to allow scientists to isolate plasma from very low volumes of mouse blood (as low as 20 µl) collected using standard microsampling techniques. A side-by-side in vitro comparison of plasma concentrations was performed using this new device and conventional sampling methods with commercial and in-house molecules. The plasma concentrations of the molecules tested were very consistent between the conventional sampling techniques and this new device/workflow. In addition, several in-life studies have also been conducted to validate this new technique as a primary PK screening tool at the Takeda Boston. The new device is simple to use and very cost effective with the added benefit that no additional training is needed for the animal technicians and the same centrifuge equipment can be employed. This device can be used for blood volumes ranging from 20 to 100 µl enabling studies not just in rat and dog but more importantly in mice.


Assuntos
Coleta de Amostras Sanguíneas/instrumentação , Afatinib , Animais , Cães , Desenho de Equipamento , Camundongos , Miniaturização/instrumentação , Quinazolinas/sangue , Radiossensibilizantes/análise , Ratos , Tamanho da Amostra
6.
ScientificWorldJournal ; 2012: 481471, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22623898

RESUMO

The concept of bonding as a positive youth development construct is reviewed in this paper. The goals are fourfold. First, theoretical perspectives of bonding are delineated. Secondly, the relationships among bonding to caregivers, friends, romantic partners, as well as teachers, and adolescents' positive developmental outcomes are reviewed. Thirdly, with theoretical and empirical support, a discussion on how to promote bonding among adolescents is offered. Finally, a critical review on the cultural issues of bonding is provided.


Assuntos
Desenvolvimento do Adolescente , Relações Interpessoais , Apego ao Objeto , Adolescente , Adulto , Cultura , Feminino , Humanos , Masculino , Psicologia do Adolescente , Fatores Sexuais
7.
Aging Ment Health ; 15(3): 414-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21491227

RESUMO

OBJECTIVES: This study aimed at testing the proposition of socioemotional selectivity theory whether older people would use more antecedent-focused emotion regulatory strategies like cognitive reappraisal but fewer response-focused strategies like suppression. It also aimed at investigating the mediating role of emotion regulation on the relationship between age and emotions. METHOD: The sample consisted of 654 younger and older adults aged between 18 and 64. RESULTS AND CONCLUSION: Results showed that age was significantly associated with positive emotions and cognitive reappraisal. No difference was found in negative emotions and suppression between younger and older adults. Cognitive reappraisal partially mediated the effect of age on positive emotions. Findings of this study contribute to our understanding of the underlying mechanism of age variations in emotional experiences.


Assuntos
Envelhecimento/psicologia , Emoções , Controle Interno-Externo , Adolescente , Adulto , Fatores Etários , Povo Asiático/psicologia , Cognição , Feminino , Hong Kong , Humanos , Masculino , Pessoa de Meia-Idade , Determinação da Personalidade , Repressão Psicológica , Inquéritos e Questionários , Adulto Jovem
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