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

Andrew E Shouksmith; Justyna M Gawel; Nabanita Nawar; Diana Sina; Yasir S Raouf; Shazreh Bukhari; Liying He; Alexandra E Johns; Pimyupa Manaswiyoungkul; Olasunkanmi O Olaoye; Aaron D Cabral; Abootaleb Sedighi; Elvin D de Araujo; Patrick T Gunning

doi:10.1021/acsmedchemlett.9b00471

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

ACS Med Chem Lett. 2019 Dec 13;11(1):56-64. doi: 10.1021/acsmedchemlett.9b00471. eCollection 2020 Jan 9.

Affiliation

¹ Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.

Abstract

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.