Deciphering the Therapeutic Potential of Novel Pentyloxyamide-Based Class I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia
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 (<b>4d</b> and <b>4m</b>) showed superior antileukemic activity compared to several approved HDACi. Furthermore, <b>4d</b> and <b>4m</b> displayed synergistic activity when combined with chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic studies showed the most promising profile for <b>4d</b> with intermediate microsomal stability, excellent plasma stability, and concentration-independent plasma protein binding. Additionally, <b>4d</b> demonstrated comparable in vivo pharmacokinetics to vorinostat. When administered in vivo, <b>4d</b> effectively inhibited the proliferation of leukemia cells without causing toxicity. Furthermore, the binding modes of <b>4d</b> and <b>4m</b> to the catalytic domain 2 of HDAC6 from <i>Danio rerio</i> were determined by X-ray crystallography.
Authors
- Thomas Kurz (ORCID: https://orcid.org/0000-0002-9474-4224)
- Bjoern B. Burckhardt (ORCID: https://orcid.org/0000-0002-1782-9937)
- Yi‐Ping Ho (ORCID: https://orcid.org/0000-0002-2052-9724)
- Arndt Borkhardt (ORCID: https://orcid.org/0000-0002-6121-4737)
- Sanil Bhatia (ORCID: https://orcid.org/0000-0001-6494-7744)
- Aleksandra A. Pandyra (ORCID: https://orcid.org/0000-0003-4794-0035)
- Katerina Scharov
- Tanja Gangnus (ORCID: https://orcid.org/0009-0005-7573-6631)
- Julian Schliehe‐Diecks (ORCID: https://orcid.org/0000-0002-7166-4950)
- Ingrid Span (ORCID: https://orcid.org/0000-0002-2892-4825)
- Holger Gohlke (ORCID: https://orcid.org/0000-0001-8613-1447)
- Matthias U. Kassack (ORCID: https://orcid.org/0000-0002-9094-8481)
- Fabian Fischer (ORCID: https://orcid.org/0000-0003-1140-2024)
- Leandro A. Alves Avelar (ORCID: https://orcid.org/0000-0001-7394-3286)
- Jia‐Wey Tu
- Paweł Stachura
- Nadine Horstick
- Titus Watrin (ORCID: https://orcid.org/0009-0003-2665-9639)
- Marie Kemkes
- Lukas Biermann
- Katharina Daugs
- Josefa Kremeyer
- Mara Hebeis
Institutions
- Forschungszentrum Jülich (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Münster (DE)
- University Hospital Bonn (DE)
- German Center for Infection Research (DE)
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02024
- Citations
- 9
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- Deutsche Forschungsgemeinschaft