RESUMO
With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Indazóis/farmacologia , Indazóis/farmacocinética , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/farmacocinética , Sulfonamidas/farmacologia , Sulfonamidas/farmacocinética , Sulfonas/farmacologia , Sulfonas/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Linhagem Celular Tumoral , Sistema Livre de Células , Córnea/patologia , Relação Dose-Resposta a Droga , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Indazóis/administração & dosagem , Indazóis/sangue , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Sulfonas/administração & dosagem , Sulfonas/sangue , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Células Cultivadas , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Indazóis , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/química , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Sulfonamidas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Anilinoalkynylpyrimidines were prepared and evaluated as dual EGFR/ErbB2 kinase inhibitors. A preference was found for substituted phenyl and heteroaromatic rings attached to the alkyne. In addition, the presence of a potential hydrogen bond donor appended to this ring was favored. Selected molecules in the series demonstrated some activity against human tumor cell lines.
Assuntos
Alcinos/química , Receptores ErbB/antagonistas & inibidores , Pirimidinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
A series of dianilinopyrimidineureas demonstrate potency as VEGFR2 kinase inhibitors.