Deciphering\nthe Therapeutic Potential of Novel Pentyloxyamide-Based\nClass I, IIb HDAC Inhibitors against Therapy-Resistant Leukemia

Histone deacetylase inhibitors (HDACi) are established\nanticancer\ndrugs, especially in hematological cancers. This study aimed to design,\nsynthesize, and evaluate a set of HDACi featuring a pentyloxyamide\nconnecting unit linker region and substituted phenylthiazole cap groups.\nA structural optimization program yielded HDACi with nanomolar inhibitory\nactivity against histone deacetylase class I/IIb enzymes. The novel\ninhibitors (<b>4d</b> and <b>4m</b>) showed superior antileukemic\nactivity compared to several approved HDACi. Furthermore, <b>4d</b> and <b>4m</b> displayed synergistic activity when combined\nwith chemotherapeutics, decitabine, and clofarabine. In vitro pharmacokinetic\nstudies showed the most promising profile for <b>4d</b> with\nintermediate microsomal stability, excellent plasma stability, and\nconcentration-independent plasma protein binding. Additionally, <b>4d</b> demonstrated comparable in vivo pharmacokinetics to vorinostat.\nWhen administered in vivo, <b>4d</b> effectively inhibited the\nproliferation of leukemia cells without causing toxicity. Furthermore,\nthe binding modes of <b>4d</b> and <b>4m</b> to the catalytic\ndomain 2 of HDAC6 from Danio rerio were\ndetermined by X-ray crystallography.