RESUMO
The hedgehog (Hh) signaling pathway is involved in diverse aspects of cellular events. Aberrant activation of Hh signaling pathway drives oncogenic transformation for a wide range of cancers, and it is therefore a promising target in cancer therapy. In the principle of association and ring-opening, we designed and synthesized a series of Hh signaling pathway inhibitors with phenyl imidazole scaffold, which were biologically evaluated in Gli-Luc reporter assay. Compound 25 was identified to possess high potency with nanomolar IC50 , and moreover, it preserved the inhibition against wild-type and drug-resistant Smo-overexpressing cells. A molecular modeling study of compound 25 expounded its binding mode to Smo receptor, providing a basis for the further structural modification of phenyl imidazole analogs.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Proteínas Hedgehog/antagonistas & inibidores , Imidazóis/química , Transdução de Sinais/efeitos dos fármacos , Anilidas/farmacologia , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Imidazóis/metabolismo , Imidazóis/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Piridinas/farmacologia , Receptor Smoothened/antagonistas & inibidores , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Relação Estrutura-AtividadeRESUMO
Aberrant hedgehog (Hh) signaling is implicated in the development of a variety of cancers. Smoothened (Smo) protein is a bottleneck in the Hh signal transduction. The regulation of the Hh signaling pathway to target the Smo receptor is a practical approach for development of anticancer agents. We report herein the design and synthesis of a series of 2-methoxybenzamide derivatives as Hh signaling pathway inhibitors. The pharmacological data demonstrated that compound 21 possessed potent Hh pathway inhibition with a nanomolar IC50 value, and it prevented Shh-induced Smo from entering the primary cilium. Furthermore, mutant Smo was effectively suppressed via compound 21. The in vitro antiproliferative activity of compound 21 against a drug-resistant cell line gave encouraging results.