Hedgehog (Hh) proteins, important regulators of development, bind the cell-surface protein Patched, allowing activation of the GPCR-like receptor, 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. LDE225 is an Hh signaling pathway inhibitor that acts by antagonizing SMO (IC50s = 1.3 and 2.5 nM for mouse and human, respectively). A dose of 20 mg/kg/day LDE225 has been shown to penetrate the blood brain barrier, inhibit Gli1 mRNA expression, and prevent tumor growth in a medulloblastoma allograft mouse model. This compound has been investigated in phase II clinical trials for potential treatment of several Hh pathway activated cancers.
