Design and biological evaluation of phenyl imidazole analogs as hedgehog signaling pathway inhibitors

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. A series of hedgehog signaling pathway antagonists with phenyl imidazole scaffold were designed on the basis of ring‐opening and association strategy. Compound 25 exhibited high potency on hedgehog pathway inhibition, and suppressed drug‐resistant Smo mutant in a concentration‐dependent manner.