RESUMO
A series of 2-anilino substituted 4-aryl-8H-purines were prepared as potent inhibitors of PDK1, a serine-threonine kinase thought to play a role in the PI3K/Akt signaling pathway, a key mediator of cancer cell growth, survival and tumorigenesis. The synthesis, SAR and ADME properties of this series of compounds are discussed culminating in the discovery of compound 6 which possessed sub-micromolar cell proliferation activity and 65% oral bioavailability in mice.
Assuntos
Compostos de Anilina/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Purinas/química , Bibliotecas de Moléculas Pequenas/química , Compostos de Anilina/farmacologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Purinas/farmacologia , Piruvato Desidrogenase Quinase de Transferência de Acetil , Bibliotecas de Moléculas Pequenas/farmacologia , SolubilidadeRESUMO
Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity against PDK1 in a biochemical enzyme assay.