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.

刺猬（Hh）信号通路是抗癌治疗的广泛关注的目标。但是，平滑化受体（SMO）的耐药性和下游/独立于SMO的Hh激活严重限制了SMO拮抗剂的临床应用。在这里，我们讨论了最近建立的抑制Hh途径并绕过上述限制的主要策略。特别是，我们回顾了为开发能够调节SMO耐药形式的新型有效SMO拮抗剂，发现有效的神经胶质瘤相关癌基因（GLI）拮抗剂和GLI介导的转录抑制剂以及建立和建立新的SMO拮抗剂所付出的努力。该方法有望在较低的单个剂量下将多种药物与增强的Hh抑制作用结合使用。