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

doi:10.1021/acs.jmedchem.1c00242

	Development of Potent NEDD8-Activating Enzyme Inhibitors Bearing a Pyrimidotriazole Scaffold
	Xiong, Chaodong 1,2,3; Zhou, Lina 1,3; Tan, Jing 1,2,3; Song, Shanshan 1,3; Bao, Xubin 1,3; Zhang, Ning 1,3; Ding, Huaqian 1,3; Zhao, Jiannan 1,2,4; He, Jin-Xue 1,3; Miao, Ze-Hong 1,3
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-05-13
卷号	64 期号:9 页码:6161-6178
ISSN号	0022-2623
DOI	10.1021/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.
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关键词	SUBSTRATE-ASSISTED INHIBITION ; UBIQUITIN-ACTIVATING ENZYME ; E3 LIGASE ; DEGRADATION ; MLN4924 ; NEDD8 ; APOPTOSIS ; IDENTIFICATION ; CONJUGATION ; LEUKEMIA
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000651785800052
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297197]
专题	中国科学院上海药物研究所
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.