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Design, synthesis and pharmacological evaluation of 2,3-dihydrobenzo-furan IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma

文献类型：期刊论文

作者Chen, Yun2; Ning, Yi3,4; Chen, Zhiwei4,5; Xue, Yaping3,4,6; Wu, Qingyun2; Duan, Wenhu4,5; Ding, Jian3,4,6; Zhou, Jinpei7; Xie, Hua1,3,4,6; Zhang, Huibin2
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-08-05
卷号256页码:16
关键词Apoptosis Diffuse large B-Cell lymphoma Interleukin-1 receptor associated kinase 4 Structure-based drug design 2 3-Dihydrobenzofuran
ISSN号0223-5234
DOI10.1016/j.ejmech.2023.115453
通讯作者Zhou, Jinpei(zhjp@cpu.edu.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Zhang, Huibin(zhanghb80@cpu.edu.cn)
英文摘要Interleukin-1 receptor associated kinase 4 (IRAK4) is a critical mediator of MYD88 L265P-induced NF-xB activation, indicating it is a promising therapeutic target for diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of 2,3-dihydrobenzofuran IRAK4 inhibitors through structure-based drug design. The representative compound 22 exhibited strong IRAK4 inhibitory potency (IRAK4 IC50 = 8.7 nM), favorable kinase selectivity and high antiproliferative activity against the MYD88 L265P DLBCL cell line (OCI-LY10 IC50 = 0.248 mu M). Compound 22 also exhibited the ability to inhibit the activation of IRAK4 signaling pathway and induce apoptosis in MYD88 L265P DLBCL cell line. In combination with Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, 22 showed enhanced apoptosis-inducing effect and antiproliferative potency. The most advanced compound 22 in this inhibitor series holds promise for further development into efficacious and selective IRAK4 inhibitors for the treatment of DLBCL.
WOS关键词KINASE
资助项目Lingang Laboratory ; [LG202103-02-08]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001006184700001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/306221]  
专题新药研究国家重点实验室
通讯作者Zhou, Jinpei; Xie, Hua; Zhang, Huibin
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
2.China Pharmaceut Univ, Ctr Drug Discovery, Jiangsu Key Lab Drug Discovery Metab Dis, 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, 19A Yuquan Rd, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
7.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,Chen, Zhiwei,et al. Design, synthesis and pharmacological evaluation of 2,3-dihydrobenzo-furan IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,256:16.
APA Chen, Yun.,Ning, Yi.,Chen, Zhiwei.,Xue, Yaping.,Wu, Qingyun.,...&Zhang, Huibin.(2023).Design, synthesis and pharmacological evaluation of 2,3-dihydrobenzo-furan IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,256,16.
MLA Chen, Yun,et al."Design, synthesis and pharmacological evaluation of 2,3-dihydrobenzo-furan IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 256(2023):16.

入库方式： OAI收割

来源：上海药物研究所

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