title: Targeting GLI factors to inhibit the Hedgehog pathway.
abstract: 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.
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Infante
authors.affiliation: Department of Molecular Medicine, "La Sapienza" University, 00161 Rome, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Alfonsi
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, "La Sapienza" University, 00161 Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Botta
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy. Electronic address: mattia.mori@iit.it.
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy; Department of Molecular Medicine, "La Sapienza" University, 00161 Rome, Italy; Pasteur Institute/Cenci Bolognetti Foundation, Rome, Italy. Electronic address: lucia.dimarcotullio@uniroma1.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
keywords: GLI antagonists; Hedgehog pathway; cancer; drug discovery