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 pre-clinical 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.