RESUMO
In this study we report on the specificity profiling of the MAP kinase inhibitors 1, 2, and 3 in a panel of 78 protein kinases including the MAPK isoforms p38(alpha,beta,gamma,delta), JNK1/2/3, and ERK1/2/8 showing 3-(4-fluorophenyl)-4-pyridin-4-ylquinolin-2(1H)-one (1) to be highly selective for p38alphaMAPK with an IC(50) of 1.8 microM. In contrast, besides p38alpha the isoxazoles 2 and 3 significantly inhibited JNK2/3 and further kinases beyond the MAPK family such as PKA, PKD, Lck, and CK1. By using sequence alignment and homology models of different members of the MAPK family the binding mode determining selectivity of 1 for the p38alpha isoform was investigated. For lead optimization of 1 a straightforward tandem-Buchwald-aldol synthetic approach toward the flexible decoration of the quinolin-2(1H)-one scaffold was employed. SAR for derivatives of 1 at the isolated p38alphaMAPK are presented.
Assuntos
Compostos de Bifenilo/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Compostos de Bifenilo/química , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Isoenzimas , Proteína Quinase 14 Ativada por Mitógeno/química , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Moleculares , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Glycogen synthase kinase 3 (GSK3) is a genetically validated drug target for human African trypanosomiasis (HAT), also called African sleeping sickness. We report the synthesis and biological evaluation of aminopyrazole derivatives as Trypanosoma brucei GSK3 short inhibitors. Low nanomolar inhibitors, which had high selectivity over the off-target human CDK2 and good selectivity over human GSK3ß enzyme, have been prepared. These potent kinase inhibitors demonstrated low micromolar levels of inhibition of the Trypanosoma brucei brucei parasite grown in culture.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Técnicas de Química Sintética , Quinase 2 Dependente de Ciclina/química , Quinase 2 Dependente de Ciclina/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Modelos Moleculares , Conformação Proteica , Pirazóis/química , Pirazóis/uso terapêutico , Especificidade por SubstratoRESUMO
Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible with hinge-region binding, and docked into a panel of protein kinases. Fragments with a high consensus score were subsequently short-listed for synthesis. Application of this strategy led to a number of core fragments with no previously reported activity against kinases. Small libraries around the core fragments were synthesized, and representative compounds were tested against a large panel of protein kinases and subjected to co-crystallization experiments. Each of the tested compounds was active against at least one kinase, but not all kinases in the panel were inhibited. A number of compounds showed high ligand efficiencies for therapeutically relevant kinases; among them were MAPKAP-K3, SRPK1, SGK1, TAK1, and GCK for which only few inhibitors are reported in the literature.