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

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 properties revealed that LSH‐A54 binds tightly to HDAC1 in an induced‐fit mechanism. The potent HDAC1/2 inhibitory properties were reflected by attenuated cell migration in a modified wound healing assay and reduced cell viability in a clonogenic survival assay in selected breast cancer cell lines.