RESUMO
Abelson kinase (c-Abl) is a ubiquitously expressed, nonreceptor tyrosine kinase which plays a key role in cell differentiation and survival. It was hypothesized that transient activation of c-Abl kinase via displacement of the N-terminal autoinhibitory "myristoyl latch", may lead to an increased hematopoietic stem cell differentiation. This would increase the numbers of circulating neutrophils and so be an effective treatment for chemotherapy-induced neutropenia. This paper describes the discovery and optimization of a thiazole series of novel small molecule c-Abl activators, initially identified by a high throughput screening. Subsequently, a scaffold-hop, which exploited the improved physicochemical properties of a dihydropyrazole analogue, identified through fragment screening, delivered potent, soluble, cell-active c-Abl activators, which demonstrated the intracellular activation of c-Abl in vivo.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Pirazóis/farmacologia , Tiazóis/farmacologia , Animais , Sítios de Ligação , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-abl/química , Proteínas Proto-Oncogênicas c-abl/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/metabolismoRESUMO
A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 1012 members composed of 4-20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed.
Assuntos
Biblioteca de Peptídeos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Proteínas Virais/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Aminoácidos/química , DNA/química , Avaliação Pré-Clínica de Medicamentos/métodos , Terapia de Alvo Molecular , Peptídeos Cíclicos/genética , Reação em Cadeia da Polimerase , Vírus Sinciciais Respiratórios , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/química , Proteína Supressora de Tumor Von Hippel-Lindau/químicaRESUMO
The pharmaceutical industry has traditionally targeted the inhibition of dysregulated kinases to treat diseases such as cancer and inflammatory disorders. In contrast to the human genome sequencing project, which aimed to identify novel biological targets, the possibility of activating kinases uses known targets in a novel manner. In an approach that is similar to other target classes (eg, GPCRs and nuclear receptors), transient upregulation of kinase function using small molecules has been increasingly demonstrated to lead to favorable disease outcomes. This review discusses direct small-molecule kinase activators: specifically, how these molecules were discovered, characterized, evaluated and developed into drug leads. The choice of potential targets, the mechanisms of activation and the common strategies used to discover activators are also highlighted.
Assuntos
Descoberta de Drogas , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Regulação Alostérica , Animais , Aurora Quinases , Desenho de Fármacos , Ativação Enzimática , Ativadores de Enzimas/química , Glucoquinase/química , Humanos , Estrutura Molecular , Fosforilação , Conformação Proteica , Proteína Quinase C/metabolismo , Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Receptor de Insulina/metabolismo , Relação Estrutura-AtividadeRESUMO
Various situations are explored in which the nickel(0)-catalyzed enyne-epoxide reductive coupling was utilized to access key intermediates towards the total synthesis of (-)-cyatha-3,12-diene (1). Enantioenriched 3,5-dien-1-ols with a variety of functionality were obtained in a straightforward manner from easily accessible 1,3-enynes and terminal epoxides.
RESUMO
The synthesis of a triglycosylated helical foldamer based on a combination of cyclopentyl- and pyrrolidinyl-based amino acids is described. This structure is stable in water, maintaining as it does a series of carbohydrate units in proximity to one another, and represents the basis of a new approach to the study of carbohydrate-carbohydrate interactions.