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Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma

文献类型：期刊论文

作者Liang, Xuewu1,2; Sun, Chenxia3,4; Li, Chunpu1,2; Yu, Haolan3,4; Wei, Xiaohui1,2; Liu, Xuyi1,2; Bao, Wei3,4; Shi, Yuqiang1,2; Sun, Xiaochen3,4; Khamrakulov, Mirzadavlat1,2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-07-08
卷号64期号:13页码:9217-9237
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c00466
通讯作者Yang, Chenghua(chenghua-yang@qq.com) ; Liu, Hong(hliu@mail.shcnc.ac.cn)
英文摘要Development of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors is of great value and significance in the treatment of neoplastic disorders and inflammatory and autoimmune diseases. However, there is a lack of effective MALT1 inhibitors in clinic. Herein, a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives were first identified and designed through high-throughput screening. We demonstrated that compounds 15c, 15e, and 20c effectively inhibited the MALT1 protease and displayed selective cytotoxicity to activated B cell-like diffuse large B cell lymphoma with low single-digit micromolar potency. Furthermore, compound 20c specifically repressed NF-.B signaling and induced cell apoptosis in MALT1-dependent TMD8 cells in a dose-dependent manner. More importantly, 20c showed good pharmacokinetic properties and antitumor efficacy with no significant toxicity in the TMD8 xenograft tumor model. Collectively, this study provides valuable lead compounds of MALT1 inhibitors for further structural optimization and antitumor mechanism study.
WOS关键词NF-KAPPA-B ; PROTEASE ; ACTIVATION ; CLEAVAGE ; IBRUTINIB ; PROTEINS ; PROMOTES ; CYLD ; KEY
资助项目National Natural Science Foundation of China[21907102] ; National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[21877118] ; National Natural Science Foundation of China[91953108] ; National Natural Science Foundation of China[21977106] ; National Natural Science Foundation of China[81903434] ; National Natural Science Foundation of China[81473245] ; National Natural Science Foundation of China[81772695] ; Science and Technology Commission of Shanghai Municipality[18JC1411304] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19431908100] ; Science and Technology Commission of Shanghai Municipality[19431901000] ; 100 Talent Programfrom Chinese Academy of Science ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020352]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000672729800021
源URL[http://119.78.100.183/handle/2S10ELR8/296984]  
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.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Second Mil Med Univ, Changhai Hosp, Dept Urol, Shanghai 200043, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, CAS Key Lab Tissue Microenvironm & Tumor, Shanghai 200031, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Liang, Xuewu,Sun, Chenxia,Li, Chunpu,et al. Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(13):9217-9237.
APA Liang, Xuewu.,Sun, Chenxia.,Li, Chunpu.,Yu, Haolan.,Wei, Xiaohui.,...&Liu, Hong.(2021).Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma.JOURNAL OF MEDICINAL CHEMISTRY,64(13),9217-9237.
MLA Liang, Xuewu,et al."Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma".JOURNAL OF MEDICINAL CHEMISTRY 64.13(2021):9217-9237.

入库方式： OAI收割

来源：上海药物研究所

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