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Discovery of Pteridine-7(8H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK)

文献类型：期刊论文

作者Dou, Dou2; Diao, Yanyan2; Sha, Wenjie2; Su, Rongrong2; Tong, Linjiang1; Li, Wenjie2; Leng, Limin2; Xie, Lijuan2; Yu, Zhixiao2; Song, Haoming2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-02-10
卷号65期号:3页码:2694-2709
ISSN号0022-2623
DOI10.1021/acs.jmedchem.1c02208
通讯作者Chen, Zhuo(chenzhuo@ecust.edu.cn) ; Li, Honglin(hlli@ecust.edu.cn) ; Xu, Yufang(yfxu@ecust.edu.cn)
英文摘要Bruton's tyrosine kinase (BTK) is an attractive therapeutic target in the treatment of cancer, inflammation, and autoimmune diseases. Covalent and noncovalent BTK inhibitors have been developed, among which covalent BTK inhibitors have shown great clinical efficacy. However, some of them could produce adverse effects, such as diarrhea, rash, and platelet dysfunction, which are associated with the off-target inhibition of ITK and EGFR. In this study, we disclosed a series of pteridine-7(8H)-one derivatives as potent and selective covalent BTK inhibitors, which were optimized from 3z, an EGFR inhibitor previously reported by our group. Among them, compound 24a exhibited great BTK inhibition activity (IC50 = 4.0 nM) and high selectivity in both enzymatic (ITK >250-fold, EGFR >2500-fold) and cellular levels (ITK >227-fold, EGFR 27-fold). In U-937 xenograft models, 24a significantly inhibited tumor growth (TGI = 57.85%) at a 50 mg/kg dosage. Accordingly, 24a is a new BTK inhibitor worthy of further development.
WOS关键词B-CELL DEVELOPMENT ; TEC FAMILY ; IBRUTINIB ; ORELABRUTINIB
资助项目National Natural Science Foundation of China[81825020] ; National Key Research and Development Program[2016YFA0502304] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project[21S11907900] ; Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project[20S11901000] ; Fundamental Research Funds for the Central Universities ; National Program for Special Supports of Eminent Professionals ; National Program for Support of Top-notch Young Professionals
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000797933300064
源URL[http://119.78.100.183/handle/2S10ELR8/301419]  
专题新药研究国家重点实验室
通讯作者Chen, Zhuo; Li, Honglin; Xu, Yufang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China
推荐引用方式
GB/T 7714		 Dou, Dou,Diao, Yanyan,Sha, Wenjie,et al. Discovery of Pteridine-7(8H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK)[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(3):2694-2709.
APA Dou, Dou.,Diao, Yanyan.,Sha, Wenjie.,Su, Rongrong.,Tong, Linjiang.,...&Xu, Yufang.(2022).Discovery of Pteridine-7(8H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK).JOURNAL OF MEDICINAL CHEMISTRY,65(3),2694-2709.
MLA Dou, Dou,et al."Discovery of Pteridine-7(8H)-one Derivatives as Potent and Selective Inhibitors of Bruton's Tyrosine Kinase (BTK)".JOURNAL OF MEDICINAL CHEMISTRY 65.3(2022):2694-2709.

入库方式： OAI收割

来源：上海药物研究所

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