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Development of Potent MALT1 Inhibitors Featuring a Novel "2-Thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one" Scaffold for the Treatment of B Cell Lymphoma

文献类型：期刊论文

作者Liang, Xuewu5,6; Yu, Haolan3,4; Liang, Renwen5,6; Feng, Zhuanghui4; Saidahmatov, Abdusaid5,6; Sun, Chenxia3,4; Ren, Hairu2,5,6; Wei, Xiaohui5,6; Zhao, Jiayan2,5,6; Yang, Chenghua1,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-02-13
卷号67期号:4页码:2884-2906
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c02031
通讯作者Yang, Chenghua(chenghua-yang@qq.com) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) has emerged as a novel and promising therapeutic target for the treatment of lymphomas and autoimmune diseases. Herein, we reported a new class of MALT1 inhibitors featuring a novel "2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one" scaffold developed by structure-based drug design. Structure-activity relationship studies finally led to the discovery of MALT1 inhibitor 10m, which covalently and potently inhibited MALT1 protease with the IC50 value of 1.7 mu M. 10m demonstrated potent and selective antiproliferative activity against ABC-DLBCL and powerful ability to induce HBL1 apoptosis. 10m also effectively downregulated the activities of MALT1 and its downstream signal pathways. Furthermore, 10m induced upregulation of mTOR and PI3K-Akt signals and exhibited a synergistic antitumor effect with Rapamycin in HBL1 cells. More importantly, 10m remarkably suppressed the tumor growth both in the implanted HBL1 and TMD8 xenograft models. Collectively, this work provides valuable MALT1 inhibitors with a distinct core structure.
WOS关键词ANALOGS ; IDENTIFICATION ; PROTEASE ; BCL10 ; KEY
资助项目National Natural Science Foundation of China[21907102] ; National Natural Science Foundation of China[81772695] ; National Natural Science Foundation of China[82273766] ; National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[2022YFA1302900] ; National Natural Science Foundation of China[LG202103-02-07] ; National Natural Science Foundation of China[LG-QS-202205-09] ; National Key R&D Program of China
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001167257500001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/309901]  
专题新药研究国家重点实验室
通讯作者Yang, Chenghua; Liu, Hong
作者单位1.Shanghai Key Lab Cell Engn, Shanghai 200433, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Shanghai Inst Biol Sci,CAS Key Lab Tissue Microenv, Shanghai 200031, Peoples R China
4.Second Mil Med Univ, Changhai Hosp, Dept Urol, Shanghai 200043, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liang, Xuewu,Yu, Haolan,Liang, Renwen,et al. Development of Potent MALT1 Inhibitors Featuring a Novel "2-Thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one" Scaffold for the Treatment of B Cell Lymphoma[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(4):2884-2906.
APA Liang, Xuewu.,Yu, Haolan.,Liang, Renwen.,Feng, Zhuanghui.,Saidahmatov, Abdusaid.,...&Liu, Hong.(2024).Development of Potent MALT1 Inhibitors Featuring a Novel "2-Thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one" Scaffold for the Treatment of B Cell Lymphoma.JOURNAL OF MEDICINAL CHEMISTRY,67(4),2884-2906.
MLA Liang, Xuewu,et al."Development of Potent MALT1 Inhibitors Featuring a Novel "2-Thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one" Scaffold for the Treatment of B Cell Lymphoma".JOURNAL OF MEDICINAL CHEMISTRY 67.4(2024):2884-2906.

入库方式： OAI收割

来源：上海药物研究所

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