Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90

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, Xiao Li Xu

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10498-10519
Number of pages22
JournalJournal of medicinal chemistry
Volume59
Issue number23
DOIs
StatePublished - Dec 8 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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