化学
喹啉
小分子
生物利用度
赖氨酸
药理学
组蛋白
甲基转移酶
结构-活动关系
组蛋白甲基转移酶
组合化学
生物化学
体外
甲基化
氨基酸
基因
医学
有机化学
作者
Hairong Tang,Aisong Yu,Xing Li,Xiaoyu Chen,Huaqian Ding,Hong Yang,Zilan Song,Qiongyu Shi,Meiyu Geng,Xun Huang,Ao Zhang
标识
DOI:10.1021/acs.jmedchem.2c01920
摘要
The histone lysine methyltransferase NSD2 is overexpressed, translocated, or mutated in multiple types of cancers and has emerged as an attractive therapeutic target. However, the development of small-molecule NSD2 inhibitors is still in its infancy, and selective and efficacious NSD2 inhibitors are highly desirable. Here, in view of the structural novelty of the reported NSD2 inhibitor DA3003-1, we conducted a comprehensive structural optimization based on the quinoline-5,8-dione scaffold. Compound 15a was identified possessing both high NSD2 inhibitory activity and potent anti-proliferative effects in the cell. Meanwhile, compound 15a has an excellent pharmacokinetic profile with high oral bioavailability. Further, this compound was found to display significant antitumor efficacy with desirable safety profile in the multiple myeloma xenograft mice models, thus warranting it as a promising candidate for further investigation.
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