Synthesis of 2-methoxybenzamide derivatives and evaluation of their hedgehog signaling pathway inhibition

Aberrant hedgehog (Hh) signaling is implicated in the development of a variety of cancers. Smoothened (Smo) protein is a bottleneck in the Hh signal transduction. The regulation of the Hh signaling pathway to target the Smo receptor is a practical approach for development of anticancer agents. We re...

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Bibliographic Details
Published in:RSC advances 2021-06, Vol.11 (37), p.2282-22825
Main Authors: Sun, Chiyu, Zhang, Dajun, Luan, Tian, Wang, Youbing, Zhang, Wenhu, Lin, Lin, Jiang, Meihua, Hao, Ziqian, Wang, Ying
Format: Article
Language:English
Subjects:
Anticancer properties
Chemistry
Kinases
Signal transduction
Signaling
Synthesis
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Summary:Aberrant hedgehog (Hh) signaling is implicated in the development of a variety of cancers. Smoothened (Smo) protein is a bottleneck in the Hh signal transduction. The regulation of the Hh signaling pathway to target the Smo receptor is a practical approach for development of anticancer agents. We report herein the design and synthesis of a series of 2-methoxybenzamide derivatives as Hh signaling pathway inhibitors. The pharmacological data demonstrated that compound 21 possessed potent Hh pathway inhibition with a nanomolar IC 50 value, and it prevented Shh-induced Smo from entering the primary cilium. Furthermore, mutant Smo was effectively suppressed via compound 21 . The in vitro antiproliferative activity of compound 21 against a drug-resistant cell line gave encouraging results. Benzamide analog ( 21 ) was identified as a potent hedgehog signaling pathway inhibitor that targeted the Smo receptor and blocked Daoy cell proliferation.
ISSN:2046-2069
2046-2069
DOI:10.1039/d1ra00732g