Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN, 47405, USA.
Medical Sciences, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN, 47405, USA.
Drug Saf. 2019 Feb;42(2):263-279. doi: 10.1007/s40264-018-0777-5.
The hedgehog pathway, for which sonic hedgehog (Shh) is the most prominent ligand, is highly conserved and is tightly associated with embryonic development in a number of species. This pathway is also tightly associated with the development of several types of cancer, including basal cell carcinoma (BCC) and acute promyelocytic leukemia, among many others. Inactivating mutations in Patched-1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types, but most prominent in BCC. This has led to the development of several compounds targeting this pathway as a cancer therapeutic. These compounds target the inducers of this pathway in Smoothened (SMO) and the GLI transcription factors, although targeting SMO has had the most success. Despite the many attempts at targeting this pathway, only three US FDA-approved drugs for cancers affect the Shh pathway. Two of these compounds, vismodegib and sonidegib, target SMO to suppress signaling from either PTCH1 or SMO mutations that lead to upregulation of the pathway. The other approved compound is arsenic trioxide, which can suppress this pathway at the level of the GLI proteins, although current evidence suggests it also has other targets. This review focuses on the safety and tolerability of these clinically approved drugs targeting the Shh pathway, along with a discussion on other Shh pathway inhibitors being developed.
刺猬通路，其最显著的配体是 sonic hedgehog (Shh)，在许多物种中高度保守，与胚胎发育紧密相关。该通路也与包括基底细胞癌 (BCC) 和急性早幼粒细胞白血病在内的多种癌症的发展密切相关。在几种癌症类型中，经常出现 Patched-1 (PTCH1) 的失活突变，导致配体非依赖性通路激活，但在 BCC 中最为突出。这导致了针对该通路的几种化合物作为癌症治疗药物的开发。这些化合物针对 Smoothened (SMO) 和 GLI 转录因子中的通路诱导物，尽管靶向 SMO 已取得了最大的成功。尽管针对该通路进行了许多尝试，但只有三种美国 FDA 批准的癌症药物会影响 Shh 通路。这两种化合物，vismodegib 和 sonidegib，靶向 SMO 以抑制导致通路上调的 PTCH1 或 SMO 突变引起的信号转导。另一种批准的化合物是三氧化二砷，它可以在 GLI 蛋白水平上抑制该通路，尽管目前的证据表明它还有其他靶点。这篇综述重点介绍了针对 Shh 通路的这些临床批准药物的安全性和耐受性，以及正在开发的其他 Shh 通路抑制剂的讨论。
