Target: Sonic Hedgehog (Shh)


The Sonic Hedgehog (Shh) signaling pathway, which is essential for proper embryonic development, has been implicated in diseases such as basal cell carcinoma, pancreatic cancer, and developmental disorders.  In this pathway, the extracellular protein Shh is activated (ShhN), binds to the transmembrane receptor Patched (Ptc1), which reverses its inhibitory effect on Smoothened (Smo).  Smo then activates Gli transcription factors, which regulate the expression of target genes including Gli1 and Ptc1.  Robotnikinin, a small molecule modulator of ShhN, has been discovered using Small Molecule Microarray (SMM) technology.  It binds ShhN with a KD of 3.1µM (SPR), and shows dose-dependent inhibition of the Shh pathway (luciferase reporter assay).  Robotnikinin also inhibits transcription of Shh-induced genes Gli1 and Gli2 in human primary keratinocytes and a synthetic model of human skin (qPCR).  This inhibitory effect is reversed when a known Smo agonist is added. Stanton et al., Nature Chemical Biology, 5, 154-156 (2009).