RESUMO
The strategy of inhibiting angiogenesis, specifically by targeting vascular endothelial growth factor receptor 2 (VEGFR-2), has been proven effective in tumor treatment. In this study, we designed several VEGFR-2 kinase inhibitors based on an indazole scaffold. Among them, the most potent compound, 30, inhibits VEGFR-2 (IC50 = 1.24 nM) with subtle selectivity over other kinases. It demonstrates significant inhibitory activity against HUVEC angiogenesis and inhibits cell migration in a dose-dependent manner. Additionally, it exhibits low acute toxicity in mice. In vivo studies, compound 30 demonstrates favorable pharmacokinetic profiles. It suppresses tumor angiogenesis in the zebrafish subintestinal vessel model, indicating that it may be a potential angiogenesis inhibitor for further development.
Assuntos
Inibidores da Angiogênese , Movimento Celular , Desenho de Fármacos , Células Endoteliais da Veia Umbilical Humana , Indazóis , Inibidores de Proteínas Quinases , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Peixe-Zebra , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Indazóis/farmacologia , Indazóis/síntese química , Indazóis/química , Humanos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Camundongos , Relação Estrutura-Atividade , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estrutura Molecular , Proliferação de Células/efeitos dos fármacosRESUMO
Synovial angiogenesis is essential for the development of rheumatoid arthritis (RA). Human vascular endothelial growth factor receptor 2 tyrosine kinase (VEGFR2) is a direct target gene that is notably elevated in RA synovium. Herein, we report the identification of indazole derivatives as a novel class of potent VEGFR2 inhibitors. The most potent compound, compound 25, displayed single-digit nanomolar potency against VEGFR2 in biochemical assays and achieved good selectivity for other protein kinases in the kinome. In addition, compound 25 dose-dependently inhibited the phosphorylation of VEGFR2 in Human Umbilical Vein Endothelial Cells (HUVECs) and showed an anti-angiogenic effect, as evidenced by the inhibition of capillary-like tube formation in vitro. Moreover, compound 25 reduced the severity and development of adjuvant-induced arthritis in rats by inhibiting synovial VEGFR2 phosphorylation and angiogenesis. Overall, these findings provide evidence that compound 25 is a leading potential drug candidate for anti-arthritic and anti-angiogenic therapy.
