Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska.
Med Res Rev. 2019 May;39(3):1137-1204. doi: 10.1002/med.21555. Epub 2018 Nov 28.
Hedgehog (Hh) signaling is involved in the initiation and progression of various cancers and is essential for embryonic and postnatal development. This pathway remains in the quiescent state in adult tissues but gets activated upon inflammation and injuries. Inhibition of Hh signaling pathway using natural and synthetic compounds has provided an attractive approach for treating cancer and inflammatory diseases. While the majority of Hh pathway inhibitors target the transmembrane protein Smoothened (SMO), some small molecules that target the signaling cascade downstream of SMO are of particular interest. Substantial efforts are being made to develop new molecules targeting various components of the Hh signaling pathway. Here, we have discussed the discovery of small molecules as Hh inhibitors from the diverse chemical background. Also, some of the recently identified natural products have been included as a separate section. Extensive structure-activity relationship (SAR) of each chemical class is the focus of this review. Also, clinically advanced molecules are discussed from the last 5 to 7 years. Nanomedicine-based delivery approaches for Hh pathway inhibitors are also discussed concisely.
刺猬（Hh）信号通路参与多种癌症的发生和发展，对于胚胎和出生后的发育至关重要。该通路在成人组织中处于静止状态，但在炎症和损伤时被激活。使用天然和合成化合物抑制 Hh 信号通路为治疗癌症和炎症性疾病提供了一种有吸引力的方法。虽然大多数 Hh 通路抑制剂针对跨膜蛋白 Smoothened（SMO），但一些针对 SMO 下游信号级联的小分子特别引人注目。人们正在努力开发针对 Hh 信号通路各个组成部分的新分子。在这里，我们从不同的化学背景讨论了小分子作为 Hh 抑制剂的发现。此外，还将一些最近鉴定的天然产物作为单独的部分包括在内。本综述的重点是每个化学类别的广泛的结构-活性关系（SAR）。还讨论了过去 5 到 7 年中临床进展的分子。还简要讨论了基于纳米医学的 Hh 通路抑制剂的递药方法。
