Improved selective class I HDAC and novel selective HDAC3 inhibitors: Beyond hydroxamic acids and benzamides

By Bresciani, Alberto; Ontoria, Jesus M.; Biancofiore, Ilaria; Cellucci, Antonella; Ciammaichella, Alina; Di Marco, Annalise; Ferrigno, Federica; Francone, Alessandra; Malancona, Savina; Monteagudo, Edith; et al
From ACS Medicinal Chemistry Letters (2019), 10(4), 481-486. Language: English, Database: CAPLUS, DOI:10.1021/acsmedchemlett.8b00517

The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcol. indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compd. RGFP966. These compds. are again based on an alternative ZBG with respect to the ortho-anilide that is featured in HDAC3 selective compds. reported to date.