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Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma

文献类型：期刊论文

作者Chen, Yun2,6; Bai, Gang3,4,5; Ning, Yi3,4; Cai, Shi2; Zhang, Tao3,4; Song, Peiran3,4; Zhou, Jinpei1; Duan, Wenhu4,6; Ding, Jian3,4; Xie, Hua3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-03-15
卷号190页码:14
关键词lnterleukin-1 receptor associated kinase 4 Imidazol1,2-6]pyridazine Diffuse large B-cell lymphoma Drug design Antitumor agents
ISSN号0223-5234
DOI10.1016/j.ejmech.2020.112092
通讯作者Xie, Hua(hxie@simm.ac.cn) ; Zhang, Huibin(zhanghb80@163.com)
英文摘要Harboring MYD88 L265P mutation triggers tumors growth through the activation of NF-kappa B by interleukin-1 receptor associated kinase 4 (IRAK4) in diffuse large B-cell lymphoma (DLBCL), highlighting IRAK4 as a therapeutic target for tumors driven by aberrant MYD88 signaling. Herein, we report the design, synthesis, and structure-activity relationships of imidazo[1,2-b]pyridazines as potent IRAK4 inhibitors. The representative compound 5 exhibited excellent IRAK4 potency (IRAK4 IC50 = 1.3 nM) and favorable kinase selectivity profile. It demonstrated cellular selectivity for activated B cell-like (ABC) subtype DLBCL with MYD88 L265P mutation in cytotoxicity assay. The kinase inhibitory efficiency of compound 5 was further validated by Western blot analysis of phosphorylation of IRAK4 and downstream signaling in OCI-LY10 and TMD8 cells. Besides, combination of compound 5 and BTK inhibitor ibrutinib synergistically reduced the viability of TMD8 cells. These results indicated that compound 5 could be a promising IRAK4 inhibitor for the treatment of mutant MYD88 DLBCL (C) 2020 Elsevier Masson SAS. All rights reserved.
WOS关键词BACTERIAL-INFECTIONS ; POOR-PROGNOSIS ; CHEMORESISTANCE ; INTERLEUKIN-1 ; ACTIVATION ; DISCOVERY ; POTENT
资助项目China National Key Hi-Tech innovation Project for the R&D of Novel Drugs[2013ZX09301303-002]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000518870100007
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/281152]  
专题新药研究国家重点实验室
通讯作者Xie, Hua; Zhang, Huibin
作者单位1.China Pharmaceut Univ, Dept Med Chem, 24 Tongjiaxiang, Nanjing 210009, Peoples R China
2.China Pharmaceut Univ, State Key Lab Nat Medicines, Ctr Drug Discovery, 24 Tongjiaxiang, Nanjing 210009, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Yun,Bai, Gang,Ning, Yi,et al. Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2020,190:14.
APA Chen, Yun.,Bai, Gang.,Ning, Yi.,Cai, Shi.,Zhang, Tao.,...&Zhang, Huibin.(2020).Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,190,14.
MLA Chen, Yun,et al."Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 190(2020):14.

入库方式： OAI收割

来源：上海药物研究所

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