期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 156, 期 -, 页码 554-562出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.07.017
关键词
Hedgehog inhibitors; Synergistic effects; Isoflavones; Cancer; Smo antagonists; Gli inhibitors
资金
- Associazione Italiana Ricerca Cancro (AIRC) [IG20801]
- Ministry of University and Research (PRIN 2012-2013) [2012C5YJSK002]
- Pasteur Institute/Cenci Bolognetti Foundation Istituto Italiano di Tecnologia (IIT)
- Progetti di Ricerca di University Sapienza di Roma
- COST Action [CM1407]
Aberrant activation of the Hedgehog (Hh) pathway is responsible for the onset and progression of several malignancies. Small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector Gli1 have thus emerged recently as valuable anticancer agents. Here, we have designed, synthesized, and tested new Hh inhibitors taking advantage by the highly versatile and privileged isoflavone scaffold. The introduction of specific substitutions on the isoflavone's ring B allowed the identification of molecules targeting preferentially Smo or Gli1. Biological assays coupled with molecular modeling corroborated the design strategy, and provided new insights into the mechanism of action of these molecules. The combined administration of two different isoflavones behaving as Smo and Gli antagonists, respectively, in primary medulloblastoma (MB) cells highlighted the synergistic effects of these agents, thus paving the way to further and innovative strategies for the pharmacological inhibition of Hh signaling. (C) 2018 Elsevier Masson SAS. All rights reserved.
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