期刊
BIOORGANIC CHEMISTRY
卷 137, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2023.106580
关键词
Microtubules; Colchicine binding site inhibitor; Coumarin; Antiproliferative activities; ERK
In this study, a new coumarin-dihydroquinoxalone derivative, MY-673, was designed, synthesized, and evaluated for its anticancer potency. The results showed that MY-673 was a potent CBSI, inhibiting tubulin polymerization and significantly inhibiting the growth of cancer cells. It was also found to inhibit the ERK and TGF-beta/SMAD signaling pathways, leading to inhibition of cell proliferation, migration, and induction of apoptosis.
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 IC50 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-beta (transforming growth factor beta) /SMAD (small mother against decapentaplegic) signaling pathway using the western blotting assay. In addition, com-pound 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.
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