Smoothened (Smo), the main transducer of the Hedgehog (Hh) signaling pathway, is a promising target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been associated with mutation-related drug resistance. In this review, we outline the resistance mechanisms of Smo inhibitors and point the way for future endeavors. We focus in particular on the development of second-generation Smo inhibitors based on co-crystal structures, inhibition of downstream components, and the regulation of other interacting pathways or mediators that could compensate for the inhibitory activity of upstream inhibitors.

刺猬（Hh）信号传导途径的主要转导子-平滑化（Smo）是抗癌治疗的有希望的靶标。尽管vismodegib和sonidegib已证明可治疗基底细胞癌（BCC），但其临床应用已与突变相关的耐药性相关。在这篇综述中，我们概述了Smo抑制剂的耐药机制，并指出了今后的努力方向。我们特别专注于基于共晶体结构，对下游成分的抑制以及其他可能补偿上游抑制剂抑制活性的相互作用途径或介质的调控，开发第二代Smo抑制剂。