Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia

The HDAC inhibitor 4-tert-butyl-N-(4-(hydroxycarbamoyl)­phenyl)­benzamide (AES-350, 51) was identified as a promising preclinical candidate
for
the treatment of acute myeloid leukemia (AML), an aggressive malignancy
with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight
analogues derived from the previously discovered novel HDAC inhibitor, AES-135, compound 51 demonstrated greater HDAC
isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved
therapeutic window, and more efficient absorption through cellular
and lipid membranes. Compound 51 also demonstrated improved
oral bioavailability compared to SAHA in mouse models. A broad spectrum
of experiments, including FACS, ELISA, and Western blotting, were
performed to support our hypothesis that 51 dose-dependently
triggers apoptosis in AML cells through HDAC inhibition.