Cyclopamine and Its Derivatives for Cancer Therapeutics

In the 1950s, researchers from the United States Department of Agriculture (USDA) investigated cases of congenital cyclopia in sheep grazing in high mountain ranges in central Idaho. After nearly a decade of research, steroidal alkaloids present in the corn lily plant (Veratrum californicum) were found responsible for the induction of cyclopic-type craniofacial birth defects that occurred when Veratrum was ingested by pregnant sheep on day 14 of gestation [7]. Jervine and cyclopamine were two important teratogenic compounds isolated from Veratrum californicum (Fig. 12.1, compound 2 and 6, respectively), while numerous nonteratogenic but toxic Veratrum alkaloids were also present such as veratramine and muldamine [42–46]. Of note, the maternal ewes do not suffer ill effects from ingestion of the plants or cyclopamine [7], with birth defects being confined to a specific window of time during fetal development [103]. Because of its steroidal structure, cyclopamine was originally proposed to antagonize putative hormones involved in regulation of specific genes [42]. The pharmacology of cyclopamine remained dormant for nearly 30 years until genetic studies revealed that mutations in the Hedgehog pathway impacted development.