Smoothened
Hedgehog Pathway
Cyclopamine compound leads to cycloptic
lambs
Lee
Inhibition of the Hedgehog Pathway leads to
midline, neural tube, and limb deformities
Chiang
Simplified Overview of the Hedgehog
Pathway
SHH
PTCH-1
SMO
SUFU/PKA
GLI
SMO inhibits SUFU and PKA in order to
activate transcription factor, GLI
Sharpe
PTCH oxysterol pumping activity inhibits SMO
Corcoran
SMO is an oncogene within the Hedgehog Pathway.
SMO is a 24 kb gene with 12 exons located on the
distal arm of Chromosome 7
Xie
SMO is a seven-span transmembrane
G-protein coupled receptor
Wang
Activating mutations interfere with formation
of the polar pocket or PTCH-SMO interaction
Xie
Basal Cell Carcinoma is one of the most
common types of cancer, although rarely fatal
A direct SMO inhibitor, Vismodegib, has been
approved by the FDA for use
Sources
• Corcoran, R. B., & Scott, M. P. (2006). Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of
medulloblastoma cells. Proceedings of the National Academy of Sciences of the United States of America, 103(22), 8408–8413.
doi:10.1073/pnas.0602852103
• Chiang, C., Litingtung, Y., Lee, E., Young, K. E., & al, e. (1996). Cyclopia and defective axial patterning in mice lacking sonic hedgehog
gene function. Nature, 383(6599), 407-13. doi:http://dx.doi.org/10.1038/383407a0
• Lee, S. T., Lee, S., Welch, K., Panter, K., & Gardner, D. (07/30/2014). Journal of agricultural and food chemistry: Cyclopamine: From
cyclops lambs to cancer treatment American Chemical Society. doi:10.1021/jf5005622
• Sekulic, Aleksandar,M.D., PhD., Migden, M. R., M.D., Oro, Anthony E,M.D., PhD., Dirix, Luc,M.D., PhD., Lewis, K. D., M.D.,
Hainsworth, J. D., M.D., . . . Hauschild, A., M.D. (2012). Efficacy and safety of vismodegib in advanced basal-cell carcinoma.The New
England Journal of Medicine, 366(23), 2171-9.
• Sharpe, H. J., Hayley J Sharpe, Weiru Wang, Rami N Hannoush, & Frederic J De Sauvage. (04/01/2015). Nature chemical biology:
Regulation of the oncoprotein smoothened by small molecules Nature Publishing Group. doi:10.1038/nchembio.1776
• Wang, C., Wu, H., Katritch, V., Han, G. W., Huang, X.-P., Liu, W., … Stevens, R. C. (2013). Structure of the human smoothened
receptor 7TM bound to an antitumor agent. Nature, 497(7449), 338–343. doi:10.1038/nature12167
• Xie, J., Murone, M., Shiuh-Ming Luoh, Ryan, A., & al, e. (1998). Activating smoothened mutations in sporadic basal-cell
carcinoma.Nature, 391(6662), 90-2. doi:http://dx.doi.org/10.1038/34201