Discovery of 1,2,4-triazine dithiocarbamate derivatives as NEDDylation agonists to inhibit gastric cancers

NEDDylation process regulates multiple physiological functions and signaling pathways, which are still in an equilibrium that favors the survival and proliferation of tumor cells. Unlike inhibitors, NEDDylation agonists are rarely studied. In this work, novel 1,2,4-triazine-dithiocarbamate derivativ...

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Published in:European journal of medicinal chemistry 2021-12, Vol.225, p.113801-113801, Article 113801
Main Authors: Song, Jian, Liu, Yuan, Yuan, Xin-Ying, Liu, Wen-Bo, Li, Yin-Ru, Yu, Guang-Xi, Tian, Xin-Yi, Zhang, Yan-Bing, Fu, Xiang-Jing, Zhang, Sai-Yang
Format: Article
Language:English
Subjects:
1 2 4-triazine
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antiproliferative activity
Cell Proliferation - drug effects
Dithiocarbamate
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
Gastric cancers
Humans
Molecular Structure
NEDDylation
Stomach Neoplasms - drug therapy
Stomach Neoplasms - metabolism
Stomach Neoplasms - pathology
Structure-Activity Relationship
Triazines - chemical synthesis
Triazines - chemistry
Triazines - pharmacology
Tumor Cells, Cultured
YAP
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Summary:NEDDylation process regulates multiple physiological functions and signaling pathways, which are still in an equilibrium that favors the survival and proliferation of tumor cells. Unlike inhibitors, NEDDylation agonists are rarely studied. In this work, novel 1,2,4-triazine-dithiocarbamate derivatives were synthesized and evaluated for antiproliferative activity against MGC-803, PC-3 and EC-109 cells. Among them, compound K3 displayed the most potent activity MGC-803, PC-3 and EC-109 cells with IC50 values of 2.35, 5.71 and 10.1 μM, respectively, which were more potent than 5-FU. Further cellular mechanisms suggested that compound K3 inhibited the cell viability, induced proliferation inhibition, arrested cell cycle at G2/M phase and induced cell apoptosis in MGC-803 and HGC-27 cells. Importantly, compound K3 could interact with NAE1 to promote the NEDDylation of MGC-803 and HGC-27 cells. The promotion of NEDDylation resulted in the degradation of c-IAP and YAP/TAZ, which leads to the induction of cell apoptosis and inhibition of proliferation in MGC-803 and HGC-27 cells. Therefore, as a NEDDylation agonist, compound K3 could effectively inhibit gastric cancer cells. Here, we reported NEDDylation promotion induced by compound K3, which could inhibit the cancer cell lines MGC-803 and HGC-27 and induce the cancer cell apoptosis via prompting the degradation of c-IAP and YAP/TAZ. [Display omitted] ●Novel 1,2,4-triazine dithiocarbamate derivatives were designed and prepared.●K3 as a NEDDylation agonist exhibited potent antiproliferative activity.●K3 promoted the NEDDylation, resulting in degradation of c-IAP and YAP/TAZ.●K3 inhibited gastric cancer cells via promoting degradation of c-IAP and YAP/TAZ.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2021.113801