1. Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
- Author
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Fen Jiang, Hui-Jie Wang, Yu-Hui Jin, Qiong Zhang, Zhi-Hui Wang, Jian-Min Jia, Fang Liu, Lei Wang, Qi-Chao Bao, Dong-Dong Li, Qi-Dong You, and Xiao-Li Xu
- Subjects
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MOLECULAR chaperones , *HEAT shock proteins , *SMALL molecules , *STRUCTURAL optimization , *ANTINEOPLASTIC agents - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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