Discovery of macrocyclic HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation

Bioorg Med Chem Lett. 2021 Sep 1;47:128168. doi: 10.1016/j.bmcl.2021.128168. Epub 2021 Jun 4.

Abstract

A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDACs 6 and 8. These macrocyclic HDAC inhibitors used an ethyl ketone as the zinc-binding group. Compounds 25 and 26 stood out as leads due to their low double-digit nM EC50s in the 2C4 cell-based HIV latency reactivation assay. The PK profiles of these macrocyclic HDAC inhibitors still needed improvement.

Keywords: HDAC inhibitor; HIV infection; HIV latency reactivation; Macrocycle; Selective HDAC inhibitor.

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HIV / drug effects*
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Histone Deacetylase Inhibitors
  • Isoenzymes
  • Histone Deacetylases