RESUMO
BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.
Assuntos
Desenho de Fármacos , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Administração Oral , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
Bruton's Tyrosine Kinase (BTK) is one of the crucial kinases for the B cell maturation and mast cell activation, and specific inhibitors of BTK are considered to be attractive targets in drug discovery research. In this Letter, we have designed and synthesized a new fluorescent probe for TR-FRET-based high-throughput screening, to identify compounds that preferentially bind to an inactive conformation of BTK which has a unique structural feature. A set of kinase-focused compound library was screened using this assay method, and compound 31 was successfully identified as a potent inhibitor which preferentially bind to the inactive conformation of BTK. These results suggest that this screening method has a great potential for the discovery of novel selective BTK inhibitors.
Assuntos
Bioensaio/métodos , Corantes Fluorescentes/química , Inibidores de Proteínas Quinases/isolamento & purificação , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Ligação Competitiva , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Concentração Inibidora 50 , Modelos Biológicos , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de ProteínaRESUMO
BTK has emerged as a promising target for treating B-cell malignancies and autoimmune diseases, and there has been a growing demand to identify selective BTK inhibitors efficiently. In this Letter, we have designed and synthesized a new fluorescent probe to screen compounds that preferentially bind to an unactivated state of BTK (BTK [U]). The fluorescence of the probe was turned on in the presence of BTK [U], and quenched by the addition of compounds which preferentially bind to BTK [U]. This unique fluorescent probe was successfully applied to the screening of a kinase focused compound library. The results suggest that this new method is a simple and easy-to-perform assay to screen inhibitors of BTK [U].
Assuntos
Corantes Fluorescentes/química , Proteínas Tirosina Quinases/análise , Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidoresRESUMO
Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor 13f (AS-1763) as a next-generation noncovalent BTK inhibitor. With significant efficacies in vivo tumor xenograft models, AS-1763 has advanced to phase 1 clinical trials.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Tirosina Quinase da Agamaglobulinemia/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Bruton's tyrosine kinase (BTK) is a promising drug target for the treatment of multiple diseases, such as B-cell malignances, asthma, and rheumatoid arthritis. A series of novel aminotriazines were identified as highly selective inhibitors of BTK by a scaffold-hopping approach. Subsequent SAR studies of this series using two conformationally different BTK proteins, an activated form of BTK and an unactivated form of BTK, led to the discovery of a highly selective BTK inhibitor, 4b. With significant efficacy in models in vivo and good ADME and safety profiles, 4b was advanced into preclinical studies.