RESUMO
A deconstruction of previously reported phosphoinositide 3-kinase δ (PI3Kδ) inhibitors and subsequent regrowth led to the identification of a privileged fragment for PI3Kδ, which was exploited to deliver a potent, efficient, and selective lead series with a novel binding mode observed in the PI3Kδ crystal structure.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Relação Estrutura-Atividade , Administração por Inalação , Animais , Classe Ia de Fosfatidilinositol 3-Quinase/química , Cristalografia por Raios X , Cães , Avaliação Pré-Clínica de Medicamentos , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/administração & dosagem , Ligação de Hidrogênio , Isoquinolinas/química , Células Madin Darby de Rim Canino , RatosRESUMO
A four-step process of high-quality modeling of existing data, deconstruction, identification of replacement cores, and an innovative synthetic regrowth strategy led to the rapid discovery of a novel oral series of PI3Kδ inhibitors with promising selectivity and excellent in vivo characteristics.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Doenças Respiratórias/tratamento farmacológico , Administração por Inalação , Animais , Disponibilidade Biológica , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Relação Dose-Resposta a Droga , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Doenças Respiratórias/metabolismo , Relação Estrutura-AtividadeRESUMO
IL-2-inducible tyrosine kinase (Itk) plays a key role in antigen receptor signaling in T cells and is considered an important target for anti-inflammatory drug discovery. In order to generate inhibitors with the necessary potency and selectivity, a compound that targeted cysteine 442 in the ATP binding pocket and with an envisaged irreversible mode of action was designed. We incorporated a high degree of molecular recognition and specific design features making the compound suitable for inhaled delivery. This study confirms the irreversible covalent binding of the inhibitor to the kinase by x-ray crystallography and enzymology while demonstrating potency, selectivity, and prolonged duration of action in in vitro biological assays. The biosynthetic turnover of the kinase was also examined as a critical factor when designing irreversible inhibitors for extended duration of action. The exemplified Itk inhibitor demonstrated inhibition of both TH1 and TH2 cytokines, was additive with fluticasone propionate, and inhibited cytokine release from human lung fragments. Finally, we describe an in vivo pharmacodynamic assay that allows rapid preclinical development without animal efficacy models.
Assuntos
Asma/tratamento farmacológico , Cisteína/química , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Trifosfato de Adenosina/química , Animais , Cristalografia por Raios X , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Regulação Enzimológica da Expressão Gênica , Humanos , Células Jurkat , Leucócitos Mononucleares/efeitos dos fármacos , Ligantes , Masculino , Tamanho da Partícula , Ligação Proteica , Proteínas Tirosina Quinases/química , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
In 1991, Barton and Turelli developed recursions to describe the evolution of multilocus systems under arbitrary forms of selection. This article generalizes their approach to allow for arbitrary modes of inheritance, including diploidy, polyploidy, sex linkage, cytoplasmic inheritance, and genomic imprinting. The framework is also extended to allow for other deterministic evolutionary forces, including migration and mutation. Exact recursions that fully describe the state of the population are presented; these are implemented in a computer algebra package (available on the Web at http://helios.bto.ed.ac.uk/evolgen). Despite the generality of our framework, it can describe evolutionary dynamics exactly by just two equations. These recursions can be further simplified using a "quasi-linkage equilibrium" (QLE) approximation. We illustrate the methods by finding the effect of natural selection, sexual selection, mutation, and migration on the genetic composition of a population.