Targeting GLI factors to inhibit the Hedgehog pathway

•Hh pathway is a druggable target for anticancer therapy.•Drug resistance or SMO downstream Hh activation renders SMO inhibitors ineffective.•Targeting GLI effectors is a more promising strategy against Hh-dependent tumors.•Structural requirements of GLI1/DNA interaction are a key tool in drug discovery.

Hedgehog (Hh) signaling has emerged in recent years as an attractive target for anticancer therapy because its aberrant activation is implicated in several cancers. Major progress has been made in the development of SMOOTHENED (SMO) antagonists, although they have shown several limitations due to downstream SMO pathway activation or the occurrence of drug-resistant SMO mutations. Recently, particular interest has been elicited by the identification of molecules able to hit glioma-associated oncogene (GLI) factors, the final effectors of the Hh pathway, which provide a valid tool to overcome anti-SMO resistance. Here, we review results achieved in developing GLI antagonists, explaining their mechanisms of action and highlighting their therapeutic potential. We also underline the relevance of structural details in their discovery and optimization.