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

doi:10.1021/acsmedchemlett.0c00474

	Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs
	Chen, Yun 1,2; Ning, Yi 3,4; Bai, Gang 3; Tong, Linjiang 3; Zhang, Tao 3; Zhou, Jinpei 5; Zhang, Huibin 2; Xie, Hua 3; Ding, Jian 3,4; Duan, Wenhu 1
刊名	ACS MEDICINAL CHEMISTRY LETTERS
	2021-01-14
卷号	12 期号:1 页码:82-87
关键词	IRAK4 PROTAC protein degrader scaffolding role diffuse large B-cell lymphoma
ISSN号	1948-5875
DOI	10.1021/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.
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关键词	DEGRADATION ; INTERLEUKIN-1 ; IRAK4
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000611413200009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295773]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Huibin; Xie, Hua; Ding, Jian; Duan, Wenhu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China 2.China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Med, Nanjing 210009, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, 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.