RESUMO
A novel series of (7-aryl-1,5-naphthyridin-2-yl)ureas was discovered as dual ERK2 and Aurora B kinases inhibitors. Several analogues were active at micromolar and submicromolar range against ERK2 and Aurora B, associated with very promising antiproliferative activity toward various cancer cell lines. Synthesis, structure activity relationship and docking study are reported. In vitro ADME properties and safety data are also discussed.
Assuntos
Antineoplásicos/farmacologia , Aurora Quinase B/antagonistas & inibidores , Descoberta de Drogas , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Ureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Aurora Quinase B/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
Perifosine treatment exhibits a complex molecular response including the inhibition of Akt or the induction of apoptosis via clustering of death receptors in lipid rafts. However, the molecular response can vary between different tumor entities and the contribution of each target pathway to the activity of Perifosine might be distinct depending on the tumor entity or the agent combined with Perifosine. In this review we discuss the current view on the mechanism of action of perifosine in cancer and the contribution of the molecular targets of Perifosine to its activity.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Fosforilcolina/análogos & derivados , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosforilcolina/química , Fosforilcolina/metabolismo , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Morte Celular/metabolismo , Transdução de SinaisRESUMO
As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC50 values of 13 and 107â nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.
