RESUMO
Starting from initial lead 1 containing a basic 5-substituent, optimisation of the glycolamide-derived neutral 5-substituent led to potent inhibitors of erbB2 with good pharmacokinetics. Representative compounds 19 and 21 inhibited phosphorylation of erbB2 in a mouse BT474C xenograft model after oral administration.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular , Espectroscopia de Ressonância Magnética , Camundongos , Transplante de Neoplasias , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/administração & dosagem , Quinazolinas/química , Quinazolinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Biomarker measurements have become an essential component of oncology drug development, particularly so in this era of targeted therapies. Such measurements ensure that clinical studies are testing our biological hypotheses and can help make the difficult decisions required to choose which drugs to stop developing or de-prioritise. For those drugs taken forward, biomarker measurements may also help choose the appropriate dose, schedule and patient population. In this review we discuss the intrinsic properties of biological sample based efficacy measurements and how these relate to their implementation in oncology drug development by way of points to consider and examples.
Assuntos
Biomarcadores , Desenho de Fármacos , Animais , Química Farmacêutica/métodos , Indústria Farmacêutica/métodos , HumanosRESUMO
AZD0530, an orally available Src inhibitor, demonstrated potent antimigratory and anti-invasive effects in vitro, and inhibited metastasis in a murine model of bladder cancer. Antiproliferative activity of AZD0530 in vitro varied between cell lines (IC(50) 0.2 ->10µM). AZD0530 inhibited tumor growth in 4/10 xenograft models tested and dynamically inhibited in vivo phosphorylation of Src substrates paxillin and FAK in both growth-inhibition-resistant and -sensitive xenografts. The activity of AZD0530 in NBT-II bladder cancer cells in vitro was consistent with inhibition of cell migration and stabilization of cell-cell adhesion. These data suggest a dominant anti-invasive pharmacology for AZD0530 that may limit tumor progression in a range of cancers. AZD0530 is currently in Phase II clinical trials.
Assuntos
Antineoplásicos/farmacologia , Benzodioxóis/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/antagonistas & inibidores , Administração Oral , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos Fase II como Assunto , Quinase 1 de Adesão Focal/metabolismo , Humanos , Camundongos , Camundongos Nus , Células NIH 3T3 , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Paxilina/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Nus , Transplante Heterólogo , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/patologia , Quinases da Família src/metabolismoRESUMO
Neutral 5-substituted 4-anilinoquinazolines addressed high in vivo clearance and phospholipidosis associated with previous basic compounds. A representative compound 8a inhibited tumor growth in a mouse xenograft model when co-administered with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT), and data are consistent with pharmacology primarily reflecting inhibition of erbB2 receptor tyrosine kinase.