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Open AccessArticle

A Smo/Gli Multitarget Hedgehog Pathway Inhibitor Impairs Tumor Growth

Department of Molecular Medicine, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy
Department of Chemistry and Technology of Drugs, Sapienza University, Piazzale A. Moro 5, 00161 Rome, Italy
[email protected], Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy
Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161 Rome, Italy
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy
Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti—Department of Molecular Medicine, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy
Authors to whom correspondence should be addressed.
These authors equally contributed to the work.
Cancers 2019, 11(10), 1518;
Received: 11 July 2019 / Revised: 29 September 2019 / Accepted: 2 October 2019 / Published: 9 October 2019
(This article belongs to the Special Issue Hedgehog Signaling in Cancer)
: Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a recent study, we exploited the high versatility of the natural isoflavone scaffold for targeting the Hh signaling pathway at multiple levels showing that the simultaneous targeting of Smo and Gli1 provided synergistic Hh pathway inhibition stronger than single administration. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Here, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which inhibits the Hh pathway at both upstream and downstream level. We demonstrate that this multitarget agent suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1, which is a novel mechanism of action in Hh inhibition.
Keywords: Hedgehog; cancer; multitarget; Smo; Gli1 Hedgehog; cancer; multitarget; Smo; Gli1
MDPI and ACS Style

Lospinoso Severini, L.; Quaglio, D.; Basili, I.; Ghirga, F.; Bufalieri, F.; Caimano, M.; Balducci, S.; Moretti, M.; Romeo, I.; Loricchio, E.; Maroder, M.; Botta, B.; Mori, M.; Infante, P.; Di Marcotullio, L. A Smo/Gli Multitarget Hedgehog Pathway Inhibitor Impairs Tumor Growth. Cancers 2019, 11, 1518.

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