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 (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.