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Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs

文献类型：期刊论文

作者Chen, Yun2,3; Ning, Yi1,4; Bai, Gang4; Tong, Linjiang4; Zhang, Tao4; Zhou, Jinpei5; Zhang, Huibin3; Xie, Hua4; Ding, Jian1,4; Duan, Wenhu2
刊名ACS MEDICINAL CHEMISTRY LETTERS
出版日期2021-01-14
卷号12期号:1页码:82-87
ISSN号1948-5875
关键词IRAK4 PROTAC protein degrader scaffolding role diffuse large B-cell lymphoma
DOI10.1021/acsmedchemlett.0c00474
通讯作者Zhang, Huibin(zhanghb80@163.com) ; Xie, Hua(hxie@simm.ac.cn) ; Ding, Jian(jding@simm.ac.cn) ; Duan, Wenhu(whduan@simm.ac.cn)
英文摘要Interleukin-1 receptor associated kinase 4 (IRAK4) is a promising therapeutic target for diffuse large B-cell lymphoma driven by MYD88 L265P mutant, acting both as a kinase and a scaffolding protein for downstream signaling molecules. While previous efforts to modulate IRAK4 activity with kinase inhibitors alone displayed moderate efficacy, protein degradation may offer a solution to blocking both IRAK4 kinase activity and scaffolding capabilities. To this end, the potent IRAK4 degrader 9 was discovered, and it effectively inhibited the activation of downstream NF-kappa B signaling and outperformed the parent compound 1. In addition, compound 9 displayed a substantial advantage in reduction of the viability of OCI-LY10 and TMD8 cells over the parent compound 1. These results underline the potential that eliminating both the kinase and scaffolding functions of IRAK4 may result in superior and broader efficacy than inhibiting the kinase activity alone.
WOS关键词DEGRADATION ; INTERLEUKIN-1 ; IRAK4
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020228] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-011-016] ; National Natural Science Foundation of China[21702220]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000611413200009
源URL[http://119.78.100.183/handle/2S10ELR8/295773]  
专题新药研究国家重点实验室
通讯作者Zhang, Huibin; Xie, Hua; Ding, Jian; Duan, Wenhu
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
3.China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Med, Nanjing 210009, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.China Pharmaceut Univ, Dept Med Chem, 24 Tongjiaxiang, Nanjing 210009, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Yun,Ning, Yi,Bai, Gang,et al. Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs[J]. ACS MEDICINAL CHEMISTRY LETTERS,2021,12(1):82-87.
APA Chen, Yun.,Ning, Yi.,Bai, Gang.,Tong, Linjiang.,Zhang, Tao.,...&Duan, Wenhu.(2021).Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs.ACS MEDICINAL CHEMISTRY LETTERS,12(1),82-87.
MLA Chen, Yun,et al."Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs".ACS MEDICINAL CHEMISTRY LETTERS 12.1(2021):82-87.

入库方式： OAI收割

来源：上海药物研究所

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