Targeting Hh-Gli signaling in MF. In canonical Hh-Gli signaling, 1 of the 3 ligands, Indian (Ihh), sonic (Shh), or desert Hh (Dhh), binds to the receptor patched 1 (Ptch1) which subsequently releases its tonic inhibition on the transmembrane protein smoothened (Smo). Smo then activates the Gli family zinc finger transcription factors, which translocate into the nucleus and activate expression of Hh target genes. Canonical Hh activation can be inhibited by various Smo inhibitors such as IPI-926 (saridegib), LDE-225 (sonidegib), and PF-0444991 among others. Recent evidence indicates that Gli proteins can also be activated noncanonically and directly, independent of Ptc1 and Smo. Various pathways such as EGF, AKT/PI3K, PDGF, and TGF-β signaling have been reported to directly activate Gli proteins. A direct inhibition of Gli proteins by small-molecule compounds such as Gli antagonist 61 (GANT61) have the advantage of blocking Gli proteins independent of their mechanism of activation.