Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
Shanghai Dermatology Hospital, Shanghai, China.
Drug Discov Today. 2018 Mar;23(3):704-710. doi: 10.1016/j.drudis.2018.01.012. Epub 2018 Jan 8.
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.
smoothened（Smo）是 Hedgehog（Hh）信号通路的主要转导蛋白，是癌症治疗的一个很有前途的靶点。尽管 vismodegib 和 sonidegib 已被证明对基底细胞癌（BCC）的治疗有效，但它们的临床应用与基因突变相关的耐药性有关。在这篇综述中，我们概述了 Smo 抑制剂的耐药机制，并为未来的研究指明了方向。我们特别关注基于共晶结构的第二代 Smo 抑制剂的开发、下游成分的抑制以及其他相互作用途径或介质的调控，这些途径或介质可以补偿上游抑制剂的抑制活性。
