文献类型：期刊文献

英文题名：Discovery of pyrido[3,4-b]indol-1-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors

作者：Dou, Dou[1];Sha, Wenjie[1];Diao, Yanyan[1];Su, Rongrong[1];Qiao, Yunjin[1];Yu, Zhixiao[1];Zhao, Zhenjiang[1];Li, Honglin[1];Chen, Zhuo[1];Xu, Yufang[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2022

卷号：119

外文期刊名：BIOORGANIC CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000788724600002)】；

基金：The research was supported by the National Key Research and Development Program (grant 2016YFA0502304) , the National Natural Science Foundation of China (grant 81825020, No. 81803437) and the Fundamental Research Funds for the Central Universities. Honglin Li is also sponsored by National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young Professionals.

语种：英文

外文关键词：BTK; Inhibitors; Non-covalent inhibitors; Scaffold hopping; Structure-activity relationship

摘要：Bruton's tyrosine kinase (BTK) is an attractive target for the treatment of malignancy and inflammatory/autoimmune diseases. Most of the covalent BTK inhibitors would induce off-target side effects and drug resistance. To improve the drug safety of BTK inhibitors, non-covalent inhibitors have attracted more and more attention. We designed a series of novel pyrido[3,4-b]indol-1-one derivatives (N-A and N-B) via scaffold hopping from CGI1-746. The structure-activity relationship (SAR) of the newly-synthesized compounds was explored. The results showed that compounds 12 and 18 exhibited potent enzymatic potency against BTK with IC50 values of 0.22 mu M and 0.19 mu M, respectively. In lymphoma cell lines U-937 cells and Ramos cells, compounds 12 and 18 displayed comparative antiproliferative activity with Ibrutinib. Moreover, compound 12 induced G1-phase cell cycle arrest and apoptosis in U-937 cells. And it could effectively inhibit tumor growth in U-937 xenograft mouse model (TGI = 41.90% at 50 mg/kg). In all, the new pyrido[3,4-b]indol-1-one derivatives have the antitumor potency by BTK inhibition and were worthy of further exploration.