2. Academic Validation
  3. Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia

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

Affiliation

  • 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.

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