Structure–Activity Relationships and Mechanism of Action of Small Molecule Smoothened Modulators Discovered by High-Throughput Screening and Rational Design

Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation or inhibition is considered a potential powerful tool in regenerative medicine and for the treatment of cancer. In the last years, many natural and nonnatural small molecules have been identified that are able to modulate the Hh pathway. Most of them target Smo, while only a few compounds are able to interact directly with upstream and downstream Hh pathway components. Although several compounds showed a remarkable potency and selectivity, their use induced emergence of mutated and resistant cell lines. In an attempt to find new chemical entries able to affect the Hh pathway and overcome limitation imposed by mutations and resistance, academic researchers and pharmaceutical companies are making further efforts to identify new drug-like small molecules to be included in the currently available therapeutic protocols for several types of cancers or in regenerative medicine and tissue repair.