Targeting Smoothened for Therapeutic Gain

The document reviewed the therapeutic potential of targeting the Smoothened (Smo) receptor, a key component of the Hedgehog (Hh) signaling pathway, for cancer treatment. Smo antagonists showed promise in treating Hh-linked cancers, with vismodegib being approved for metastatic basal cell carcinoma. Smo agonists were also important for understanding both canonical and noncanonical Hh signaling. The review highlighted the complexity of Smo pharmacology, including its three-dimensional structure and multiple ligand-binding sites, which could inform the design of new therapeutic agents. Noncanonical Hh signaling mechanisms, such as those involving Src kinase activation and Ca2+ spikes, were also discussed.