2. Academic Validation
  3. Discovery of novel tertiary amide derivatives as NEDDylation pathway activators to inhibit the tumor progression in vitro and in vivo

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

  • Eur J Med Chem. 2020 Apr 15;192:112153. doi: 10.1016/j.ejmech.2020.112153.
Dong-Jun Fu 1,  Jian Song 2,  Ting Zhu 2,  Xiao-Jing Pang 2,  Sheng-Hui Wang 3,  Yan-Bing Zhang 2,  Bo-Wen Wu 2,  Jun-Wei Wang 2,  Xiaolin Zi 4,  Sai-Yang Zhang 5,  Hong-Min Liu 2
Affiliations

Affiliations

  • 1 Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
  • 2 School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China.
  • 3 School of Basic Medical Science, Zhengzhou University, Zhengzhou, 450001, China.
  • 4 Departments of Urology, University of California, Irvine, 92868, USA.
  • 5 School of Basic Medical Science, Zhengzhou University, Zhengzhou, 450001, China; Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, China; School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, 450001, China; The Academy of Medical Science, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
PMID: 32135407 DOI: 10.1016/j.ejmech.2020.112153
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.

Keywords

Cancer; IAP; NEDDylation activator; Tertiary amide.

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