化学
热休克蛋白90
广告
嘧啶
热休克蛋白
体外
药理学
结构-活动关系
小分子
Hsp90抑制剂
生物化学
生物
基因
作者
Jiang Fen,Huijie Wang,Yuhui Jin,Qiong Zhang,Zhi‐Hui Wang,Jianmin Jia,Fang Liu,Lei Wang,Qichao Bao,Dongdong Li,Qidong You,Xiu Xu
标识
DOI:10.1021/acs.jmedchem.6b00912
摘要
Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
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