2. Academic Validation
  3. Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia

Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia

  • J Med Chem. 2024 Dec 12;67(23):21223-21250. doi: 10.1021/acs.jmedchem.4c02024.
Fabian Fischer 1,  Julian Schliehe-Diecks 2,  Jia-Wey Tu 2,  Tanja Gangnus 3,  Yu Lin Ho 1,  Mara Hebeis 4,  Leandro A Alves Avelar 1,  Katerina Scharov 2,  Titus Watrin 2,  Marie Kemkes 2,  Pawel Stachura 2 5,  Katharina Daugs 2,  Lukas Biermann 1,  Josefa Kremeyer 1,  Nadine Horstick 1,  Ingrid Span 4,  Aleksandra A Pandyra 2 6 7,  Arndt Borkhardt 2,  Holger Gohlke 1 8,  Matthias U Kassack 1,  Bjoern B Burckhardt 3,  Sanil Bhatia 2,  Thomas Kurz 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical und Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • 2 Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • 3 Individualized Pharmacotherapy, Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, 48149 Münster, Germany.
  • 4 Bioinorganic Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Egerlandstr. 1, 91058 Erlangen, Germany.
  • 5 Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstraße 1, 40225 Düsseldorf, Germany.
  • 6 Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Germany.
  • 7 German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, 53127 Bonn, Germany.
  • 8 Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich, 52425 Jülich, Germany.
PMID: 39602240 DOI: 10.1021/acs.jmedchem.4c02024
Abstract

Histone deacetylase inhibitors (HDACi) are established Anticancer drugs, especially in hematological cancers. This study aimed to design, synthesize, and evaluate a set of HDACi featuring a pentyloxyamide connecting unit linker region and substituted phenylthiazole cap groups. A structural optimization program yielded HDACi with nanomolar inhibitory activity against histone deacetylase class I/IIb Enzymes. The novel inhibitors (4d and 4m) showed superior antileukemic activity compared to several approved HDACi. Furthermore, 4d and 4m displayed synergistic activity when combined with chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic studies showed the most promising profile for 4d with intermediate microsomal stability, excellent plasma stability, and concentration-independent plasma protein binding. Additionally, 4d demonstrated comparable in vivo pharmacokinetics to vorinostat. When administered in vivo, 4d effectively inhibited the proliferation of leukemia cells without causing toxicity. Furthermore, the binding modes of 4d and 4m to the catalytic domain 2 of HDAC6 from Danio rerio were determined by X-ray crystallography.

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