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SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy

文献类型：期刊论文

作者Zhou, Li-Na1,2; Xiong, Chaodong1,2,3; Cheng, Yong-Jun4; Song, Shan-Shan1,2; Bao, Xu-Bin1,2; Huan, Xia-Juan1,2; Wang, Tong-Yan1,2; Zhang, Ao1,2,3; Miao, Ze-Hong1,2; He, Jin-Xue1,2,4
刊名NEOPLASIA
出版日期2022-10-01
卷号32页码:12
ISSN号1476-5586
关键词SOMCL-19-133 NAE inhibitor MLN4924 NEDD8 Oral administration
DOI10.1016/j.neo.2022.100823
通讯作者Zhang, Ao(ao6919zhang@sjtu.edu.cn) ; Miao, Ze-Hong(zhmiao@simm.ac.cn) ; He, Jin-Xue(jinxue_he@simm.ac.cn)
英文摘要Inhibition of the NEDD8-activating enzyme (NAE), the key E1 enzyme in the neddylation cascade, has been considered an attractive anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally available NAE inhibitor, which is an analog to AMP. It effectively inhibited NAE with an IC50 value of 0.36 nM and exhibited more than 2855-fold selectivity over the closely related Ubiquitin-activating enzyme (UAE). It is worth noting that treatment with SOMCL-19-133 prominently inhibited Cullin neddylation and delayed the turnover of a panel of Cullin-RING ligases (CRLs) substrates (e.g., Cdt1, p21, p27, and Weel) at lower effective concentrations than that of MLN4924, subsequently caused DNA damage and Chk1/Chk2 activation, and thus triggered cell cycle arrest and apoptosis. Moreover, SOMCL-19-133 exhibited potent antiproliferative activity against a broad range of human tumor cell lines (mean IC50 201.11 nM), which was about 5.31-fold more potent than that of MLN4924. In vivo, oral delivery treatments with SOMCL-19-133, as well as the subcutaneous injection, led to significant tumor regression in mouse xenograft models. All of the treatments were well tolerated on a continuous daily dosing schedule. Compared with MLN4924, SOMCL-19-133 had a 5-fold higher peak plasma concentration, lower plasma clearance, and a 4-fold larger area under the curve (AUC(last)). In conclusion, SOMCL-19-133 is a promising preclinical candidate for treating cancers owing to its profound in vitro and in vivo efficacy and favorable pharmacokinetic properties.
WOS关键词E3 UBIQUITIN LIGASES ; CULLIN-RING LIGASES ; ACTIVATING ENZYME ; NEDD8 ACTIVATION ; MLN4924 ; SCF ; CELLS ; IDENTIFICATION ; PEVONEDISTAT ; LEUKEMIA
资助项目National Natural Science Foundation of China[82073875] ; National Natural Science Foundation of China[82073865] ; Chinese Academy of Sciences[29201731121100101] ; Chinese Academy of Sciences[XDA12020104] ; Chinese Academy of Sciences[XDA12020109] ; Chinese Academy of Sciences[CASIMM0120185003] ; Shanghai Rising-Star Program[19QA1410900] ; State Key Laboratory of Drug Research
WOS研究方向Oncology
语种英语
出版者ELSEVIER SCIENCE INC
WOS记录号WOS:000888447500004
源URL[http://119.78.100.183/handle/2S10ELR8/304404]  
专题新药研究国家重点实验室
通讯作者Zhang, Ao; Miao, Ze-Hong; He, Jin-Xue
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing, Peoples R China
2.Chinese Acad Sci, Canc Res Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai, Peoples R China
3.Shanghai Jiao Tong Univ, Pharm X Ctr, Sch Pharm, Shanghai, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Jiangsu, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Li-Na,Xiong, Chaodong,Cheng, Yong-Jun,et al. SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy[J]. NEOPLASIA,2022,32:12.
APA Zhou, Li-Na.,Xiong, Chaodong.,Cheng, Yong-Jun.,Song, Shan-Shan.,Bao, Xu-Bin.,...&He, Jin-Xue.(2022).SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy.NEOPLASIA,32,12.
MLA Zhou, Li-Na,et al."SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy".NEOPLASIA 32(2022):12.

入库方式： OAI收割

来源：上海药物研究所

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