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

doi:10.1016/j.ejmech.2020.112092

	Design and synthesis of Imidazo[1,2-b]pyridazine IRAK4 inhibitors for the treatment of mutant MYD88 L265P diffuse large B-cell lymphoma
	Chen, Yun 1,6; Bai, Gang 2,3,4; Ning, Yi 2,3; Cai, Shi 1; Zhang, Tao 2,3; Song, Peiran 2,3; Zhou, Jinpei 5; Duan, Wenhu 3,6; Ding, Jian 2,3; Xie, Hua 2,3
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	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
DOI	10.1016/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.
资助项目	China National Key Hi-Tech innovation Project for the R&D of Novel Drugs[2013ZX09301303-002]
WOS关键词	BACTERIAL-INFECTIONS ; POOR-PROGNOSIS ; CHEMORESISTANCE ; INTERLEUKIN-1 ; ACTIVATION ; DISCOVERY ; POTENT
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000518870100007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281152]
专题	中国科学院上海药物研究所
通讯作者	Xie, Hua; Zhang, Huibin
作者单位	1.China Pharmaceut Univ, State Key Lab Nat Medicines, Ctr Drug Discovery, 24 Tongjiaxiang, Nanjing 210009, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.China Pharmaceut Univ, Dept Med Chem, 24 Tongjiaxiang, Nanjing 210009, 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.