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

Journal of medicinal chemistry

Authors: Fabian Fischer, Julian Schliehe-Diecks, Jia-Wey Tu, Tanja Gangnus, Yu Lin Ho, Mara Hebeis, Leandro A Alves Avelar, Katerina Scharov, Titus Watrin, Marie Kemkes, Pawel Stachura, Katharina Daugs, Lukas Biermann, Josefa Kremeyer, Nadine Horstick, Ingrid Span, Aleksandra A Pandyra, Arndt Borkhardt, Holger Gohlke, Matthias U Kassack, Bjoern B Burckhardt, Sanil Bhatia, Thomas Kurz

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 ( and ) showed superior antileukemic activity compared to several approved HDACi. Furthermore, and displayed synergistic activity when combined with chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic studies showed the most promising profile for with intermediate microsomal stability, excellent plasma stability, and concentration-independent plasma protein binding. Additionally, demonstrated comparable in vivo pharmacokinetics to vorinostat. When administered in vivo, effectively inhibited the proliferation of leukemia cells without causing toxicity. Furthermore, the binding modes of and to the catalytic domain 2 of HDAC6 from were determined by X-ray crystallography.

PMID: 39602240