Targeting SMO

During the 1960s, the corn lily Veratrum californicum was identified as the cause for serious birth defects that were reported to occur in the lambs of grazing pregnant sheep over a period of years.³ Cyclopamine was later identified as the active agent responsible for these birth defects in lambs due to its inhibition of the activity of Hedgehog pathway’s SMO protein during embryonic development.^4,5 Another related, naturally occurring compound, jervine, has been shown to produce similar effects.^4,5 However, cylcopamine and jervine do not have acceptable pharmaceutical properties due to their low affinity, poor water solubility, and lack of oral bioavailability.⁷ To circumvent this problem, efforts have been made to develop SMO inhibitors of a different chemical class than cyclopamine.⁶

High-throughput screenings using a reporter of GLI transcription in combination with structure-based design have been used to find novel inhibitors of the Hedgehog pathway’s SMO.⁶ Results from those efforts have led to the identification of a number of Hedgehog inhibitors with oral bioavailability, which are currently under investigation in clinical trials for the treatment of multiple malignancies.