Identification of ortho-hydroxy anilide as a novel scaffold for lysine demethylase 5 inhibitors

Bioorg Med Chem Lett. 2019 May 15;29(10):1173-1176. doi: 10.1016/j.bmcl.2019.03.028. Epub 2019 Mar 21.

Abstract

Fe(II)/α-ketoglutarate-dependent lysine demethylases (KDMs) are attractive drug targets for several diseases including cancer. In this study, we designed and screened ortho-substituted anilides that are expected to function as Fe(II) chelators, and identified ortho-hydroxy anilide as a novel scaffold for KDM5A inhibitors. Treatment of human lung cancer A549 cells with a prodrug form of 4-carboxy-2-hydroxy-formanilide (9c) increased trimethylated lysine 4 on histone H3 level, suggesting KDM5 inhibition in the cells.

Keywords: Drug design; Histone deacetylase; Inhibitor; Lysine demethylase; Small molecule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Anilides / chemistry*
  • Anilides / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Histones / metabolism
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Kinetics
  • Retinoblastoma-Binding Protein 2 / antagonists & inhibitors*
  • Retinoblastoma-Binding Protein 2 / genetics
  • Retinoblastoma-Binding Protein 2 / metabolism

Substances

  • Anilides
  • Enzyme Inhibitors
  • Histones
  • Isoenzymes
  • KDM5A protein, human
  • Retinoblastoma-Binding Protein 2