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

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.