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Discovery of novel tertiary amide derivatives as NEDDylation pathway activators to inhibit the tumor progression in vitro and in vivo.
- Source :
-
European Journal of Medicinal Chemistry . Apr2020, Vol. 192, pN.PAG-N.PAG. 1p. - Publication Year :
- 2020
-
Abstract
- NEDDylation pathway regulates multiple physiological process, unlike inhibitors, NEDDylation activators are rarely studied. Novel amide derivatives were synthesized and evaluated for antiproliferative activity against MGC803, MCF-7 and PC-3 cells. Among them, Ⅶ-31 displayed the most potent activity with an IC 50 value of 94 nmol/L against MGC803 cells. Cellular mechanisms elucidated that Ⅶ-31 inhibited the cell viability, arrested cell cycle at G2/M phase and induced apoptosis via intrinsic and extrinsic pathways against MGC803 cells. In addition, Ⅶ-31 activated NAE1-Ubc12-Cullin1 NEDDylation via interacting with NAE1 directly. Furthermore, the activation of NEDDylation resulted in the degradation of inhibitor of apoptosis proteins (IAPs). Importantly, Ⅶ-31 inhibited tumor growth in xenograft models in vivo without the apparent toxicity. In summary, it is the first time to reveal that Ⅶ-31 deserves consideration for cancer therapy as a NEDDylation activator. Image 1 • Tertiary amides were synthesized and evaluated for their anticancer activity. • It is the first time to report a NEDDylation activator. • The NEDDylation activator inhibit gastric cancer MGC803 cells. [ABSTRACT FROM AUTHOR]
- Subjects :
- *AMIDE derivatives
*CANCER invasiveness
*CELL cycle
*CANCER cells
*TUMOR growth
Subjects
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 192
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 142407318
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112153