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

Linda Schäker-Hübner, Reza Haschemi, Thomas Büch, Fabian B Kraft, Birke Brumme, Andrea Schöler, Robert Jenke, Jens Meiler, Achim Aigner, Gerd Bendas, Finn K Hansen

ChemMedChem 2022 May 04

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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 D7.4 ) 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. © 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.

Citation

Linda Schäker-Hübner, Reza Haschemi, Thomas Büch, Fabian B Kraft, Birke Brumme, Andrea Schöler, Robert Jenke, Jens Meiler, Achim Aigner, Gerd Bendas, Finn K Hansen. Balancing Histone Deacetylase (HDAC) Inhibition and Drug-likeness: Biological and Physicochemical Evaluation of Class I Selective HDAC Inhibitors. ChemMedChem. 2022 May 04;17(9):e202100755