Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors

Bioorg Med Chem Lett. 2016 Sep 15;26(18):4492-4496. doi: 10.1016/j.bmcl.2016.07.070. Epub 2016 Jul 29.

Abstract

Features from a high throughput screening (HTS) hit and a previously reported scaffold were combined to generate 1,7-naphthyridones as novel KDM5 enzyme inhibitors with nanomolar potencies. These molecules exhibited high selectivity over the related KDM4C and KDM2B isoforms. An X-ray co-crystal structure of a representative molecule bound to KDM5A showed that these inhibitors are competitive with the co-substrate (2-oxoglutarate or 2-OG).

Keywords: Epigenetics; Histone lysine demethylases; KDM5 inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Dogs
  • Drug Design
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
  • Madin Darby Canine Kidney Cells
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology*
  • Nuclear Proteins / antagonists & inhibitors*
  • Repressor Proteins / antagonists & inhibitors*
  • Retinoblastoma-Binding Protein 2 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Naphthyridines
  • Nuclear Proteins
  • Repressor Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • KDM5A protein, human
  • KDM5B protein, human
  • Retinoblastoma-Binding Protein 2