Balancing Histone Deacetylase (HDAC) Inhibition and Drug-likeness: Biological and Physicochemical Evaluation of Class I Selective HDAC Inhibitors.

ABSTRACT: Herein we report the structure-activity and structure-physicochemical property relationships of a series of class I selective ortho-aminoanilides targeting the "foot-pocket" in HDAC1&2. To balance the structural benefits and the physicochemical disadvantages of these substances, we started with a set of HDACi related to tacedinaline (CI-994) and evaluated their solubility, lipophilicity (log D_7.4 ) and inhibition of selected HDAC isoforms. Subsequently, we selected the most promising "capless" HDACi and transferred its ZBG to our previously published scaffold featuring a peptoid-based cap group. The resulting hit compound 10 c (LSH-A54) showed favorable physicochemical properties and is a potent, selective HDAC1/2 inhibitor. The following evaluation of its slow binding propertie

SUBMITTER: Schaker-Hubner L 

PROVIDER: S-EPMC9303312 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature