文献类型：期刊文献

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

作者：Dou, Dou[1];Diao, Yanyan[1];Sha, Wenjie[1];Su, Rongrong[1];Tong, Linjiang[2];Li, Wenjie[1];Leng, Limin[1];Xie, Lijuan[1];Yu, Zhixiao[1];Song, Haoming[1];Shen, Zihao[1];Zhu, Lili[1];Zhao, Zhenjiang[1];Xie, Hua[2];Chen, Zhuo[1];Li, Honglin[1];Xu, Yufang[1]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China

年份：2022

卷号：65

期号：3

起止页码：2694

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000797933300064)】；

基金：This research was supported in part by the National Natural Science Foundation of China (81825020 to H.L.); the National Key Research and Development Program (2016YFA0502304 to H.L.); the National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China (2018ZX09711002); the Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project (21S11907900 and 20S11901000 to Z.Z.); and the Fundamental Research Funds for the Central Universities. H.L. was also sponsored by the National Program for Special Supports of Eminent Professionals and the National Program for Support of Top-notch Young Professionals.

语种：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.