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

• Published in: Journal of medicinal chemistry 2024-12, Vol.67 (23), p.21223-21250
• Main Authors: Fischer, Fabian, Schliehe-Diecks, Julian, Tu, Jia-Wey, Gangnus, Tanja, Ho, Yu Lin, Hebeis, Mara, Alves Avelar, Leandro A., Scharov, Katerina, Watrin, Titus, Kemkes, Marie, Stachura, Pawel, Daugs, Katharina, Biermann, Lukas, Kremeyer, Josefa, Horstick, Nadine, Span, Ingrid, Pandyra, Aleksandra A., Borkhardt, Arndt, Gohlke, Holger, Kassack, Matthias U., Burckhardt, Bjoern B., Bhatia, Sanil, Kurz, Thomas
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacokinetics; Amides - pharmacology; Amides - therapeutic use; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Drug Resistance, Neoplasm - drug effects; Histone Deacetylase 6 - antagonists & inhibitors; Histone Deacetylase 6 - metabolism; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacokinetics; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - metabolism; Humans; Leukemia - drug therapy; Leukemia - pathology; Mice; Models, Molecular; Structure-Activity Relationship; Zebrafish
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c02024

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.