The therapeutic uses of chromatin-modifying agents

Expert Opin Ther Targets. 2007 Jun;11(6):835-51. doi: 10.1517/14728222.11.6.835.

Abstract

In contrast to genetic aberrations, epigenetic aberrations can be reversed by the use of histone acetyltransferase (HAT), histone deacetylase (HDAC), SIRT, or histone methyltransferase (HMT) inhibitors. A well-known HDACi, suberoylanilide hydroxamic acid, has been recently approved for the treatment of cutaneous T cell lymphoma, and a number of HDACi are in clinical trials as anticancer drugs. In addition, HDACi could be useful in antimalarial and antifungal therapies and can reactivate the HIV-1 expression in latent cellular reservoirs, thus suggesting the use in a combination therapy with highly active antiretroviral therapy. HDACi have also been reported to have anti-inflammatory effects through inhibition of cytokines and key transcription factors, and to ameliorate the phenotypes in animal models of neurological disorders. HDACi can also reactivate the gamma-globin gene for the treatment of beta-thalassaemia, and recently were shown to relieve morphological and functional effects of muscular dystrophia. Dysfunction of HAT enzymes is also often associated with several diseases, including cancer; thus, the HATi can represent new chemical entities for the development of new drugs. Only a few HMTi have been described to date, but these small molecules could be a useful scaffold to discovering new highly active and enzyme-selective compounds to develop as therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Chromatin / enzymology
  • Chromatin / genetics*
  • Chromatin / metabolism*
  • Drug Design
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / therapeutic use*
  • Histone Acetyltransferases / antagonists & inhibitors
  • Histone Deacetylase Inhibitors
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Humans
  • Protein Methyltransferases

Substances

  • Chromatin
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histone Methyltransferases
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Histone Acetyltransferases