Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 178, Issue -, Pages 177-194Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.05.072
Keywords
Imidazo[4,5-c]pyridin-2-one; Tubulin polymerization; Katanin; Antitumor
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Funding
- National Natural Science Foundation of China [21877015, 21790333]
- Key Research Program of Frontier Sciences, CAS [QYZDY-SSW-SLH012]
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Microtubule is one of the important targets for cancer treatment. A novel class of diaryl substituted imidazo[4,5-c]pyridin-2-ones and imidazo[4,5-c]pyridines were designed based on combination principles by merging the structures of beta-lactams and purine-type compounds known as tubulin polymerization inhibitor and katanin activity up-regulator, respectively. Their antitumor activities were evaluated in vitro and the mechanism was elucidated, leading to the identification of 1,6-diaryl-1H-imidazo[4,5-c]pyridin-2(3H)-one 20b as the first bifunctional agent that can target both tubulin and katanin simultaneously. The in vivo assays verified that compound 20b significantly inhibited xenograft tumor growth with good pharmacokinetic characteristics, demonstrating a promising potential for further development into anti-tumor drug candidates with a unique mechanism of dual-targeting microtubule. (C) 2019 Elsevier Masson SAS. All rights reserved.
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