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.
Andrew E Shouksmith  1 ,  Justyna M Gawel  1 ,  Nabanita Nawar  1 ,  Diana Sina  1 ,  Yasir S Raouf  1 ,  Shazreh Bukhari  1 ,  Liying He  1 ,  Alexandra E Johns  1 ,  Pimyupa Manaswiyoungkul  1 ,  Olasunkanmi O Olaoye  1 ,  Aaron D Cabral  1 ,  Abootaleb Sedighi  1 ,  Elvin D de Araujo  1 ,  Patrick T Gunning  1
Affiliations
  • 1. Department of Chemical and Physical Sciences, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, Ontario L5L 1C6, Canada.
PMID: 31938464 DOI: 10.1021/acsmedchemlett.9b00471
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.

Products