Abstract
The Hedgehog (Hh) signaling pathway plays important roles in the tumorigenesis of multiple cancers and is a key target for drug discovery. In a screen of natural products extracted from Chinese herbs, we identified eight ent-Kaurane diterpenoids and two triterpene dilactones as novel Hh pathway antagonists. Epistatic analyses suggest that these compounds likely act at the level or downstream of Smoothened (Smo) and upstream of Suppressor of Fused (Sufu). The ent-Kauranoid-treated cells showed elongated cilia, suppressed Smo trafficking to cilia, and mitotic defects, while the triterpene dilactones had no effect on the cilia and ciliary Smo. These ent-Kaurane diterpenoids provide new prototypes of Hh inhibitors, and are valuable probes for deciphering the mechanisms of Smo ciliary transport and ciliogenesis.
Highlights
The Hedgehog (Hh) pathway plays fundamental roles in embryonic development, and aberrantly activated Hh signaling drives the formation of multiple cancers, basal cell carcinoma (BCC) and medulloblastoma (MB) [1]
Major progress has been made in the development of small molecules that inhibit the Hh signaling pathway
Several of which are being tested in clinical trials for the treatment of multiple types of cancer [2]
Summary
The Hedgehog (Hh) pathway plays fundamental roles in embryonic development, and aberrantly activated Hh signaling drives the formation of multiple cancers, basal cell carcinoma (BCC) and medulloblastoma (MB) [1]. Major progress has been made in Hh pathway targeted cancer therapies with Hh pathway antagonists (HPAs). Several Smoothened (Smo) antagonists are in clinical trials for treating a variety of cancers. Vismodegib (GDC–0449, Roche) is the first HPA approved by the FDA for treating BCC [2]. Acquired resistance to vismodegib was soon observed in MB and BCC patients, resulting in cancer relapse [3, 4]. It has been widely suggested to develop new HPAs that target different molecules
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