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
  • 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.
Products