Journal
NATURAL PRODUCT REPORTS
Volume 33, Issue 5, Pages 595-601Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5np00153f
Keywords
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Funding
- National Institutes of Health [R01 GM113100]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM113100, P50GM107615] Funding Source: NIH RePORTER
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During the 1950s, sheep ranchers in the western United States experienced episodic outbreaks of cyclopic lambs. In this highlight I describe how these mysterious incidents were traced to the grazing of Veratrum californicum wildflowers by pregnant ewes, leading to the discovery of cyclopamine (1) as a plant-derived teratogen. The precise mechanism of cyclopamine action remained enigmatic for 30 years, until this steroid alkaloid was found to be the first specific inhibitor of Hedgehog (Hh) signalling and a direct antagonist of the transmembrane receptor Smoothened (SMO). In addition to being a valuable probe of Hh pathway function, cyclopamine has been used to demonstrate the therapeutic potential of Hh pathway inhibitors. I discuss the development of SMO antagonists as anticancer therapies and emerging challenges.
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