2. Academic Validation
  3. Synthesis of Peptoid-Based Class I-Selective Histone Deacetylase Inhibitors with Chemosensitizing Properties

Synthesis of Peptoid-Based Class I-Selective Histone Deacetylase Inhibitors with Chemosensitizing Properties

  • J Med Chem. 2019 Dec 26;62(24):11260-11279. doi: 10.1021/acs.jmedchem.9b01489.
Viktoria Krieger 1,  Alexandra Hamacher 1,  Fangyuan Cao 2,  Katharina Stenzel 1,  Christoph G W Gertzen 1 3 4,  Linda Schäker-Hübner 5,  Thomas Kurz 1,  Holger Gohlke 1 3,  Frank J Dekker 2,  Matthias U Kassack 1,  Finn K Hansen 5
Affiliations

Affiliations

  • 1 Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf , Universitätsstr. 1 , 40225 Düsseldorf , Germany.
  • 2 Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy , University of Groningen , Antonius Deusinglaan 1 , 9713 AV Groningen , The Netherlands.
  • 3 John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), and Institute for Complex Systems - Structural Biochemistry (ICS-6) , Forschungszentrum Jülich GmbH , Wilhelm-Johnen-Straße , 52425 Jülich , Germany.
  • 4 Center for Structural Studies (CSS) , Heinrich-Heine-Universität Düsseldorf , Universitätsstr. 1 , 40225 Düsseldorf , Germany.
  • 5 Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Medical Faculty , Leipzig University , Brüderstraße 34 , 04103 Leipzig , Germany.
PMID: 31762274 DOI: 10.1021/acs.jmedchem.9b01489
Abstract

There is increasing evidence that histone deacetylase (HDAC) inhibitors can (re)sensitize Cancer cells for chemotherapeutics via "epigenetic priming". In this work, we describe the synthesis of a series of class I-selective HDAC inhibitors with 2-aminoanilides as zinc-binding groups. Several of the synthesized compounds revealed potent inhibition of the class I HDAC isoforms HDAC1, HDAC2, and/or HDAC3 and promising antiproliferative effects in the human ovarian Cancer cell line A2780 and the human squamous carcinoma cell line Cal27. Selected compounds were investigated in a cellular model of platinum resistance. In particular, compound 2a revealed potent chemosensitizing properties and full reversal of cisplatin resistance in Cal27CisR cells. This effect is related to a synergistic increase in Caspase 3/7 activation and induction of Apoptosis. Thus, this work demonstrates that pan-HDAC inhibition or dual class I/class IIb inhibition is not required for full reversal of cisplatin resistance.

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