title: Inhibition of Hedgehog-dependent tumors and cancer stem cells by a newly identified naturally occurring chemotype.
abstract: Hedgehog (Hh) inhibitors have emerged as valid tools in the treatment of a wide range of cancers. Indeed, aberrant activation of the Hh pathway occurring either by ligand-dependent or -independent mechanisms is a key driver in tumorigenesis. The smoothened (Smo) receptor is one of the main upstream transducers of the Hh signaling and is a validated target for the development of anticancer compounds, as underlined by the FDA-approved Smo antagonist Vismodegib (GDC-0449/Erivedge) for the treatment of basal cell carcinoma. However, Smo mutations that confer constitutive activity and drug resistance have emerged during treatment with Vismodegib. For this reason, the development of new effective Hh inhibitors represents a major challenge for cancer therapy. Natural products have always represented a unique source of lead structures in drug discovery, and in recent years have been used to modulate the Hh pathway at multiple levels. Here, starting from an in house library of natural compounds and their derivatives, we discovered novel chemotypes of Hh inhibitors by mean of virtual screening against the crystallographic structure of Smo. Hh functional based assay identified the chalcone derivative 12 as the most effective Hh inhibitor within the test set. The chalcone 12 binds the Smo receptor and promotes the displacement of Bodipy-Cyclopamine in both Smo WT and drug-resistant Smo mutant. Our molecule stands as a promising Smo antagonist able to specifically impair the growth of Hh-dependent tumor cells in vitro and in vivo and medulloblastoma stem-like cells and potentially overcome the associated drug resistance.
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291 Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Infante
authors.affiliation: Department of Molecular Medicine, Sapienza Università di Roma, Viale Regina Elena 291, Rome, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Alfonsi
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291 Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Ingallina
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, Rome, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Quaglio
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ghirga
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: D'Acquarica
authors.affiliation: Department of Molecular Medicine, Sapienza Università di Roma, Viale Regina Elena 291, Rome, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Bernardi
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Di Magno
authors.affiliation: Department of Molecular Medicine, Sapienza Università di Roma, Viale Regina Elena 291, Rome, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Canettieri
authors.affiliation: Department of Molecular Medicine, Sapienza Università di Roma, Viale Regina Elena 291, Rome, Italy.|Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza Università di Roma, Viale Regina Elena 291, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Molecular Medicine, Sapienza Università di Roma, Viale Regina Elena 291, Rome, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Botta
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291 Rome, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Molecular Medicine, Sapienza Università di Roma, Viale Regina Elena 291, Rome, Italy.|Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza Università di Roma, Viale Regina Elena 291, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D000072086:Smoothened Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047188:Chalcones; D053823:Hedgehog Proteins; D054852:Small Molecule Libraries; D000072086:Smoothened Receptor