ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Hedgehog Proteins/antagonists & inhibitors , Imidazoles/chemistry , Signal Transduction/drug effects , Anilides/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Binding Sites , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Hedgehog Proteins/metabolism , Humans , Imidazoles/metabolism , Imidazoles/pharmacology , Ligands , Molecular Docking Simulation , Pyridines/pharmacology , Smoothened Receptor/antagonists & inhibitors , Smoothened Receptor/genetics , Smoothened Receptor/metabolism , Structure-Activity RelationshipABSTRACT
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.
