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Structure-based optimization of indoline-containing compounds as second generation inhibitors of NF-KB-inducing kinase (NIK)

文献类型：期刊论文

作者Cheng, Jing5,6,7; Yan, Ziqin6,7; Li, Xinzhi4; Liu, Chen3,6,7; Tong, Linjiang6,7; Lyu, Xilin6,7; Yang, Bingjie5,6,7; Chen, Zheng4; Zhao, Yujun1,2,3,5,6,7
刊名JOURNAL OF MOLECULAR STRUCTURE
出版日期2024-01-05
卷号1295页码:19
关键词Kinase inhibitor NIK NF-KB2 Indoline COT Cytotoxicity
ISSN号0022-2860
DOI10.1016/j.molstruc.2023.136755
通讯作者Chen, Zheng(chenzheng@hit.edu.cn) ; Zhao, Yujun(yjzhao@simm.ac.cn)
英文摘要Overactivation of NIK led to increased transcriptional activity of NF-KB2, which was associated with human metabolic diseases, immunological disorders, and cancer. Therefore, NIK inhibitors were pursued as a potential treatment of NIK-driven human diseases. The first generation of NIK inhibitors features propargylic alcohol moieties, which were metabolic soft spots that led to the discovery of a second generation of NIK inhibitors without a propargylic alcohol. In this study, a series of compounds were designed, synthesized, and evaluated as novel NIK inhibitors using a NIK kinase assay. To evaluate selectivity profiles of these inhibitors, the most potent compound 50 was tested over COT and other two panels of 31 kinases. In addition, 50 inhibited NIK-driven upregulation of CCL5 gene in primary hepatocytes and showed low cytotoxicity against normal kidney cells HEK-293. These attributes make 50 a promising candidate for future optimization aimed to increase potency and selectivity against NIK and NF-KB2 pathway.
WOS关键词KAPPA-B PATHWAY ; POTENT ; DISCOVERY ; ALPHA ; LIVER ; INFLAMMATION ; HEALTH
资助项目National Natural Science Foundation of China[82073682] ; National Natural Science Foundation of China[81872724] ; National Natural Science Foundation of China[82273759] ; Jinan Innovation Team Project[2021GXRC069] ; Science and Technology Commission of Shanghai Municipality[22ZR1474500]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001087434400001
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/307536]  
专题新药研究国家重点实验室
通讯作者Chen, Zheng; Zhao, Yujun
作者单位1.Shandong Acad Pharmaceut Sci, Shandong Prov Key Lab Biopharmaceut, Jinan 250101, Peoples R China
2.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
4.Harbin Inst Technol, HIT Ctr Life Sci, Sch Life Sci & Technol, Harbin 150001, Peoples R China
5.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Small Mol Drug Res Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Cheng, Jing,Yan, Ziqin,Li, Xinzhi,et al. Structure-based optimization of indoline-containing compounds as second generation inhibitors of NF-KB-inducing kinase (NIK)[J]. JOURNAL OF MOLECULAR STRUCTURE,2024,1295:19.
APA Cheng, Jing.,Yan, Ziqin.,Li, Xinzhi.,Liu, Chen.,Tong, Linjiang.,...&Zhao, Yujun.(2024).Structure-based optimization of indoline-containing compounds as second generation inhibitors of NF-KB-inducing kinase (NIK).JOURNAL OF MOLECULAR STRUCTURE,1295,19.
MLA Cheng, Jing,et al."Structure-based optimization of indoline-containing compounds as second generation inhibitors of NF-KB-inducing kinase (NIK)".JOURNAL OF MOLECULAR STRUCTURE 1295(2024):19.

入库方式： OAI收割

来源：上海药物研究所

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