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Development of Potent NEDD8-Activating Enzyme Inhibitors Bearing a Pyrimidotriazole Scaffold

文献类型：期刊论文

作者Xiong, Chaodong1,2,3; Zhou, Lina1,3; Tan, Jing1,2,3; Song, Shanshan1,3; Bao, Xubin1,3; Zhang, Ning1,3; Ding, Huaqian1,3; Zhao, Jiannan1,2,4; He, Jin-Xue1,3; Miao, Ze-Hong1,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-05-13
卷号64期号:9页码:6161-6178
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c00242
通讯作者He, Jin-Xue(jinxue_he@simm.ac.cn) ; Miao, Ze-Hong(zhmiao@simm.ac.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn)
英文摘要The ubiquitin-like protein NEDD8 is a critical signaling molecule implicated in the functional maintenance and homeostasis of cells. Dysregulation of this process is involved in a variety of human diseases, including cancer. Therefore, NEDD8-activating enzyme E1 (NAE), the only activation enzyme of the neddylation pathway, has been an emergent anticancer target. In view of the single-agent modest response of the clinical NAE inhibitor, pevonedistat (compound 1, MLN4924), efforts on development of new inhibitors with both high potency and better safety profiles are urgently needed. Here, we report a structural hopping strategy by optimizing the central deazapurine framework and the solvent interaction region of compound 1, leading to compound 26 bearing a pyrimidotriazole scaffold. Compound 26 not only has compatible potency in the biochemical and cell assays but also possesses improved pharmacokinetic (PK) properties than compound 1. In vivo, compound 26 showed significant antitumor efficacy and good safety in xenograft models.
WOS关键词SUBSTRATE-ASSISTED INHIBITION ; UBIQUITIN-ACTIVATING ENZYME ; E3 LIGASE ; DEGRADATION ; MLN4924 ; NEDD8 ; APOPTOSIS ; IDENTIFICATION ; CONJUGATION ; LEUKEMIA
资助项目National Natural Science Foundation of China[81773565] ; National Natural Science Foundation of China[82073875] ; National Natural Science Foundation of China[82073865] ; National Natural Science Foundation of China[81703327] ; Shanghai Jiao Tong University[AF1700037] ; Shanghai Jiao Tong University[WF220217002] ; Shanghai Jiao Tong University[WH10117001]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000651785800052
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/297197]  
专题新药研究国家重点实验室
通讯作者He, Jin-Xue; Miao, Ze-Hong; Zhang, Ao
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Shanghai Jiao Tong Univ, PharmX Ctr, Sch Pharm, Shanghai 200240, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Shanghai Jiao Tong Univ, Sch Pharm, Shanghai Key Lab Mol Engn Chiral Drugs, Shanghai 200240, Peoples R China
6.Zhengzhou Univ, State Key Lab Esophageal Canc Prevent & Treatment, Minist Educ China, Zhengzhou 450001, Peoples R China
推荐引用方式
GB/T 7714		 Xiong, Chaodong,Zhou, Lina,Tan, Jing,et al. Development of Potent NEDD8-Activating Enzyme Inhibitors Bearing a Pyrimidotriazole Scaffold[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(9):6161-6178.
APA Xiong, Chaodong.,Zhou, Lina.,Tan, Jing.,Song, Shanshan.,Bao, Xubin.,...&Zhang, Ao.(2021).Development of Potent NEDD8-Activating Enzyme Inhibitors Bearing a Pyrimidotriazole Scaffold.JOURNAL OF MEDICINAL CHEMISTRY,64(9),6161-6178.
MLA Xiong, Chaodong,et al."Development of Potent NEDD8-Activating Enzyme Inhibitors Bearing a Pyrimidotriazole Scaffold".JOURNAL OF MEDICINAL CHEMISTRY 64.9(2021):6161-6178.

入库方式： OAI收割

来源：上海药物研究所

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