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

  • ChemMedChem. 2022 May 4;17(9):e202100755. doi: 10.1002/cmdc.202100755.
Linda Schäker-Hübner  1  2 ,  Reza Haschemi  2 ,  Thomas Büch  3 ,  Fabian B Kraft  2 ,  Birke Brumme  1 ,  Andrea Schöler  1 ,  Robert Jenke  3  4 ,  Jens Meiler  1 ,  Achim Aigner  3 ,  Gerd Bendas  2 ,  Finn K Hansen  2
Affiliations
  • 1. Institut für Wirkstoffentwicklung, Medizinische Fakultät, Universität Leipzig, Brüderstraße 34, 04103, Leipzig, Germany.
  • 2. Abteilung für Pharmazeutische und Zellbiologische Chemie, Pharmazeutisches Institut, Universität Bonn, An der Immenburg 4, 53121, Bonn, Germany.
  • 3. Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Klinische Pharmakologie, Medizinische Fakultät, Universität Leipzig, Härtelstraße 16-18, 04107, Leipzig, Germany.
  • 4. University Cancer Center Leipzig (UCCL), Universitätsklinikum Leipzig, Liebigstraße 22, Haus 7, 04103, Leipzig, Germany.
PMID: 35073610 DOI: 10.1002/cmdc.202100755
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 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.

Keywords
cancer; drug design; epigenetics; histone deacetylases; inhibitors.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124053
    BRD2492
    99.22%, HDAC1/2 Inhibitor
    target: HDAC
    Research Areas: Cancer