RESUMEN
Hedgehog signaling pathway inhibitors are emerging as new therapeutic intervention against cancer. A novel series of N-(2-pyrimidinylamino) benzamide derivatives as hedgehog signaling pathway inhibitors were designed and synthesized. Most compounds presented significant inhibitory effect on hedgehog signaling pathway, among which 21 compounds exhibited more potent than vismodegib. Furthermore, compound 6a showed moderate pharmacokinetic properties in vivo, representing a promising lead compound for further exploration.
Asunto(s)
Benzamidas/química , Benzamidas/farmacología , Proteínas Hedgehog/metabolismo , Pirimidinas/química , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Semivida , Proteínas Hedgehog/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Malignant tumors remain a significant health threat, with death often occurring as a result of metastasis. Cell adhesion is a crucial step in the metastatic cascade of tumor cells, and interruption of this step is considered to be a logical strategy for prevention and treatment of tumor metastasis. Celastrol [3-hydroxy-24-nor-2-oxo-1(10),3,5,7-friedelatetraen-29-oic acid], a quinone methide triterpene from the medicinal plant Tripterygium wilfordii, possesses antitumor activities, whereas the underlying mechanism(s) remains elusive. Here, we found that celastrol inhibited cell-extracellular matrix (ECM) adhesion of human lung cancer 95-D and mouse melanoma B16F10 cells. This inhibition was achieved through suppressing beta1 integrin ligand affinity and focal adhesion formation, accompanied by the reduced phosphorylation of focal adhesion kinase (FAK). In understanding the underlying mechanisms, we found that celastrol activated p38 mitogen-activated protein kinase (MAPK) by phosphorylation before the decrement of phosphorylated FAK and that this action was independent of the presence of fibronectin. Using 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), a specific inhibitor of p38 MAPK, the effects of celastrol on beta1 integrin function, cell-ECM adhesion, and phosphorylation of FAK were partially attenuated. In addition, focal adhesion-dependent cell migration and invasion were both inhibited by treatment with celastrol. Finally, the antimetastatic activity of celastrol was examined in vivo using the B16F10-green fluorescent protein-injected C57BL/6 mouse model, as indicated by decreased pulmonary metastases in celastrol-administrated mice. Taken together, these data demonstrate for the first time that celastrol exerts potent antimetastatic activity both in vitro and in vivo, and they provide new evidence for the critical roles of p38 MAPK in the regulation of integrin function and cell adhesion.