Issue 5, 2016

I only have eye for ewe: the discovery of cyclopamine and development of Hedgehog pathway-targeting drugs

Abstract

Covering: 1950s to 2015

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.

Graphical abstract: I only have eye for ewe: the discovery of cyclopamine and development of Hedgehog pathway-targeting drugs

Article information

Article type
Highlight
Submitted
08 Dec 2015
First published
20 Jan 2016

Nat. Prod. Rep., 2016,33, 595-601

Author version available

I only have eye for ewe: the discovery of cyclopamine and development of Hedgehog pathway-targeting drugs

J. K. Chen, Nat. Prod. Rep., 2016, 33, 595 DOI: 10.1039/C5NP00153F

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