文献类型：期刊文献

英文题名：Discovery of pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors

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

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

年份：2022

卷号：126

外文期刊名：BIOORGANIC CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000833467900001)】；

基金：The research is supported in part by the National Key Research and Development Program (Grant No. 2016YFA0502304) , the National Natural Science Foundation of China (Grant No. 81825020) , the Na-tional Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China (No. 2018ZX09711002) , and the Fundamental Research Funds for the Central Universities. Honglin Li is 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

外文关键词：Noncovalent BTK inhibitor; B cell malignancy; Autoimmune disorder; Tyrosine kinase inhibitor; Scaffold hopping

摘要：Bruton's tyrosine kinase (BTK) is a promising target in the treatment of B cell malignancies and autoimmune disorders. Developing selective non-covalent BTK inhibitors is an important strategy to overcome the side effects and drug resistance induced by covalent BTK inhibitors. In this article, we designed and synthesized pyrrolo [1,2-a] quinoxalin-4(5H)-one and imidazo [1,2-a] quinoxalin-4(5H)-one based selective noncovalent BTK inhibitors via scaffold hopping from BMS-986142 and investigated their biological activities. Among the synthesized compounds, pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives 2 and 4 showed great BTK inhibition potency with IC50 value at 7.41 nM and 11.4 nM, respectively. Besides, they showed equivalent or even better potency in U937 and Ramos cells than BMS-986142. The kinase selectivity profiling study illustrated the excellent selectivity of compound 2 against a panel of 468 kinases. In U937 xenograft models, compound 2 could significantly inhibit tumor growth with TGI = 65.61%. In all, we provided a new scaffold as non-covalent selective BTK inhibitors and the representative compounds exhibited potency both in vitro and in vivo.