A Smo/Gli Multitarget Hedgehog Pathway Inhibitor Impairs Tumor Growth

Cancers

Paola Infante¹  Francesca Ghirga¹  Mattia Mori²  Bruno Botta³  Deborah Quaglio³  Silvia Balducci³  Isabella Romeo³  Marta Moretti⁴  Lucia Di Marcotullio⁵  Miriam Caimano⁵  Francesca Bufalieri⁵  Ludovica Lospinoso Severini⁵  Irene Basili⁵  Marella Maroder⁵  Elena Loricchio⁵ 

[1] CLNS@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy;Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy;Department of Chemistry and Technology of Drugs, Sapienza University, Piazzale A. Moro 5, 00161 Rome, Italy;Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161 Rome, Italy;Department of Molecular Medicine, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy;

关键词: hedgehog;    cancer;    multitarget;    smo;    gli1;   

DOI  :  10.3390/cancers11101518

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown