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Discovery of a novel Coumarin-Dihydroquinoxalone derivative MY-673 as a tubulin polymerization inhibitor capable of inhibiting the ERK pathway with potent anti-gastric cancer activities.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2023 Aug; Vol. 137, pp. 106580. Date of Electronic Publication: 2023 May 02. - Publication Year :
- 2023
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Abstract
- As a class of microtubule targeting agents, colchicine binding site inhibitors (CBSIs) are considered as promising drug candidates for cancer therapy. However, due to adverse reactions, there are currently no CBSIs approved by FDA for cancer treatment. Therefore, extensive efforts are still encouraged to find novel CBSIs with different chemical structures and better anticancer efficacies. In this work, we designed and synthesized a new coumarin-dihydroquinoxalone derivative, MY-673, and evaluated its anticancer potency in vitro and in vivo. We confirmed that MY-673 was a potent CBSI that it not only inhibited tubulin polymerization, but also exhibited significant inhibitory potency on the growth of 13 cancer cells with IC <subscript>50</subscript> values from 11.7 nM to 395.9 nM. Based on the results of kinase panel screening, MY-673 could inhibit ERK (extracellular regulated protein kinases) pathways-related kinases. We further confirmed that MY-673 could inhibit ERK signaling pathway in MGC-803 and HGC-27 cells, and then affected the expression level of SMAD4 protein in TGF-β (transforming growth factor β) /SMAD (small mother against decapentaplegic) signaling pathway using the western blotting assay. In addition, compound MY-673 could effectively inhibit cell proliferation, migration and induce cell apoptosis. We also further confirmed the in vivo efficacy of MY-673 in inhibiting tumor growth using the MGC-803 xenograft tumor model. At 20 mg/kg, the TGI rate was 85.9%, and it did not cause obvious toxicity to the main organs of mice. Together, the results we report here indicated that MY-673 was a promising CBSI for cancer treatment, which was capable of inhibiting the ERK pathway with potent antiproliferative activities in vitro and in vivo.<br />Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Animals
Mice
Tubulin Modulators pharmacology
Tubulin Modulators therapeutic use
Tubulin Modulators chemistry
MAP Kinase Signaling System
Tubulin metabolism
Microtubules
Colchicine metabolism
Cell Proliferation
Cell Line, Tumor
Drug Screening Assays, Antitumor
Structure-Activity Relationship
Stomach Neoplasms drug therapy
Antineoplastic Agents chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 137
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 37149948
- Full Text :
- https://doi.org/10.1016/j.bioorg.2023.106580