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Cyclopamine and Its Derivatives for Cancer Therapeutics

  • Martin Tremblay
  • Karen McGovernEmail author
Chapter

Abstract

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.

Keywords

Minimal Residual Disease Hedgehog Pathway Gli1 Expression Steroidal Alkaloid Piperidine Nitrogen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Several data on IPI-926 summarized in this chapter were the fruit of the entire Infinity Hedgehog team who are specially acknowledged. Outstanding contributions made by Dr. Phillip A. Beachy and Dr. James K. Chen served as the starting point for Infinity’s program. In addition, we gracefully acknowledged long-standing collaborators of Infinity Pharmaceuticals, Inc. who had a major impact on the work presented in this chapter: Dr. Neil Watkins (Monash Institute of Medical Research), Dr. David A. Tuveson (Cancer Research UK), Dr. André B. Charette (University of Montreal) and Mr. Steve Monsen (USFS retiree). Finally, the authors thank Drs. Margaret A. Read, Alfredo C. Castro, and Vito J. Palombella for critical review of the manuscript.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Infinity Pharmaceuticals, Inc.CambridgeUSA

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