Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90
- J Med Chem. 2016 Dec 8;59(23):10498-10519. doi: 10.1021/acs.jmedchem.6b00912.
- 1. State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.
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.