Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity

J Med Chem. 2011 Jul 14;54(13):4928-32. doi: 10.1021/jm200453n. Epub 2011 Jun 13.

Abstract

Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4-hydroxybenzylidene)piperidin-4-one (7g) and its analogues 8a-l. Among them, 7g, 8e, and 8l displayed high and selective CARM1 inhibition, with lower or no activity against a panel of different PRMTs or HKMTs. In human LNCaP cells, 7g showed a significant dose-dependent reduction of the PSA promoter activity.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Epigenesis, Genetic
  • HEK293 Cells
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Methylation
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Poly(A)-Binding Protein I / genetics
  • Poly(A)-Binding Protein I / metabolism
  • Promoter Regions, Genetic
  • Prostate-Specific Antigen / genetics
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Protein-Arginine N-Methyltransferases / genetics
  • Structure-Activity Relationship

Substances

  • Piperidines
  • Poly(A)-Binding Protein I
  • Luciferases
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1
  • Prostate-Specific Antigen