Figure 2.
The canonical HH-signalling pathway and pharmacological inhibitors targeting this pathway that are under ongoing development as anticancer therapies. The HH-processing pathway involves HHC autocatalysis, and SKN and Dispatched proteins, which mediate the release of HHN ligands (IHH, DHH and SHH). In the absence of HHN binding, PTCH interacts with and inhibits the activity of SMO; HHN binding to PTCH releases its inhibitory effects on SMO, resulting in SMO accumulation and sequestration of COS and SUFU proteins in cilia, which releases the GLI transcription factors to exert their effects in the nucleus. KIF3A and β-arrestin are required for localization of SMO to cilia. GLI1/2 promote a gene-expression pattern relevant to tumorigenesis. Development of investigational anticancer agents that inhibit SMO activation is of great interest. In addition, other potential targets, such as extracellular HHN ligands, GLI1/2 activation, or inhibition of gene transcription are under preclinical investigation. Besides the FDA-approved agent vismodegib, a number of small-molecule inhibitors of SMO are currently under clinical investigation. Abbreviations: COS, Costal; DHH, Desert hedgehog; HH, Hedgehog; HHC, Hedgehog C-terminal domain; HHN, Hedgehog N-terminal domain; HIP, Hedgehog interacting protein; IHH, Indian hedgehog; Ptch, Patched; SHH, Sonic hedgehog; SKN, Skinny hedgehog; SMO, Smoothened; SUFU, suppressor of fused.