Smoothened homolog (SMO) (SMO)

Smoothened homolog (SMO) is a Class F G protein-coupled receptor that serves as a key transducer in the Hedgehog signaling pathway, a critical regulator of embryonic development and adult tissue maintenance (UniProt P59951). In the absence of Hedgehog ligands, SMO activity is constitutively repressed by the transmembrane protein Patched-1 (PTCH1); however, ligand binding to PTCH1 relieves this inhibition, allowing SMO to translocate to the primary cilium and activate GLI transcription factors (PubMed: 28543580). Aberrant activation of this pathway, often through mutations in SMO or PTCH1, is a primary driver in several malignancies, most notably basal cell carcinoma and medulloblastoma (NIH: StatPearls). Therapeutic targeting of SMO involves small-molecule inhibitors that bind to its extracellular or transmembrane domains to lock the receptor in an inactive conformation (PubChem: CID 24771162). While effective in treating Hedgehog-driven cancers, SMO inhibitors are associated with significant side effects such as muscle cramps and taste disturbances, and they carry a high risk of teratogenicity due to the pathway's role in fetal development (FDA: Erivedge Label).

Other names

SMOHSmoothened receptorFrizzled family receptorG protein-coupled receptor Smoothened

Small molecule antagonism of the Smoothened receptor, which prevents the activation of downstream GLI transcription factors and inhibits the Hedgehog signaling pathway (PubMed: 25237167).