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

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)56-64
Number of pages9
JournalACS Medicinal Chemistry Letters
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 9 2020
Externally publishedYes

Keywords

  • acute myeloid leukemia
  • enzyme inhibition
  • histone deacetylases
  • pharmacokinetics

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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