Hedgehog (hh) proteins, important regulators of development, bind the cell-surface protein Patched, allowing activation of Smoothened (Smo). In vertebrates, this ultimately leads to the activation of the zinc-finger transcription factors of the GLI family. Overactivation of this pathway contributes to certain cancers, including glioblastoma, for which the GLI proteins are named. GANT 58 is a GLI antagonist that inhibits GLI1-mediated transcription (EC50 = 5 μM) in a variety of cell types. It inhibits the hh signaling pathway downstream of Smo and the endogenous downstream inhibitor Sufu thereby affecting GLI1 nuclear accumulation. GANT 58 displays antiproliferative and antitumor activity against Ewing sarcoma family of tumor cells.
