Current trends in Hedgehog signaling pathway inhibition by small molecules

The Hedgehog (Hh) signaling pathway is a widely appreciated target for anticancer therapy. However, drug resistance at the Smoothened receptor (SMO) and Hh activation downstream/independently of SMO seriously limit the clinical use of SMO antagonists. Here, we address the main strategies that have been recently established to inhibit the Hh pathway and to bypass the above limitations. Particularly, we review efforts that have been spent to develop novel and potent SMO antagonists able to modulate the drug-resistant forms of SMO, to discover efficient glioma-associated oncogene (GLI) antagonists and inhibitors of GLI-mediated transcription, and to establish and assay promising combination of multiple agents with enhanced Hh inhibition at lower individual doses.