Identification and optimization of novel 6-acylamino-2-aminoquinolines as potent Hsp90?C-terminal inhibitors

摘要

Abstract In order to discover novel Hsp90 inhibitors targeting the C-terminal ATP binding pocket, a novobiocin derivative based ROCS model was constructed for virtual screening. Compound 13 was identified as the lead compound and then systematical structure activity relationship (SAR) study was conducted. These efforts led to compound 69 , which exhibited potent anti-proliferative activities against MCF7 and SKBr3 breast cancer cell lines. In 4T1 mice breast cancer models, 69 exhibited potent tumor growth inhibition and anti-metastasis effect. Compound 69 as a potent antitumor agent targeting the Hsp90?C-terminal is worthy of further pre-clinical study. Graphical abstract Display Omitted Highlights ? A ROCS model was constructed to identify novel Hsp90?C-terminal inhibitors. ? 13 was identified as the lead compound and structure modification led to 69 . ? 69 exhibited potent cytotoxicity and suitable physicochemical properties. ? 69 exhibited tumor growth inhibition and anti-metastasis effect in 4T1 mice models.