Discovery of novel tertiary amide derivatives as NEDDylation pathway activators to inhibit the tumor progression in vitro and in vivo

European Journal of Medicinal Chemistry
Dong-Jun FuHong-Min Liu

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 IC50 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.

Citations

Nov 25, 2020·Bioorganic & Medicinal Chemistry·Shu-Yu WangSai-Yang Zhang
Feb 19, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Qianqian SongHong-Min Liu
Aug 30, 2021·European Journal of Medicinal Chemistry·Jian SongSai-Yang Zhang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Related Papers

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Imanol Zubiete-FrancoMaría L Martínez-Chantar
Biochemical and Biophysical Research Communications
Lihui LiLijun Jia
Cellular & Molecular Immunology
Kun Han, Jiyan Zhang
© 2021 Meta ULC. All rights reserved