Discovery of spirohydantoins as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases

Bioorg Med Chem Lett. 2021 May 1:39:127854. doi: 10.1016/j.bmcl.2021.127854. Epub 2021 Feb 23.

Abstract

p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.

Keywords: CBP; Histone acetyltransferase; P300; Spirohydantoin.

Publication types

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

MeSH terms

  • Administration, Oral
  • Biological Availability
  • CREB-Binding Protein / antagonists & inhibitors*
  • CREB-Binding Protein / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • E1A-Associated p300 Protein / antagonists & inhibitors*
  • E1A-Associated p300 Protein / metabolism
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydantoins / administration & dosage
  • Hydantoins / metabolism
  • Hydantoins / pharmacology*
  • Molecular Structure
  • Spiro Compounds / administration & dosage
  • Spiro Compounds / metabolism
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Hydantoins
  • Spiro Compounds
  • CREB-Binding Protein
  • CREBBP protein, human
  • E1A-Associated p300 Protein
  • EP300 protein, human