HDAC8: a multifaceted target for therapeutic interventions

  • Trends Pharmacol Sci. 2015 Jul;36(7):481-92. doi: 10.1016/j.tips.2015.04.013.
Alokta Chakrabarti  1 Ina Oehme  2 Olaf Witt  3 Guilherme Oliveira  4 Wolfgang Sippl  5 Christophe Romier  6 Raymond J Pierce  7 Manfred Jung  8
Affiliations
  • 1. Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 2. Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
  • 3. Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Centre (DKFZ), Heidelberg, Germany; Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany.
  • 4. Genomics and Computational Biology Group, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
  • 5. Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
  • 6. Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM, Illkirch, France.
  • 7. Center for Infection and Immunity of Lille (CIIL), INSERM U1019 - CNRS UMR 8204, Université de Lille, Institut Pasteur de Lille, Lille, France.
  • 8. Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany. Electronic address: [email protected].
Abstract

Histone deacetylase 8 (HDAC8) is a class I histone deacetylase implicated as a therapeutic target in various diseases, including Cancer, X-linked intellectual disability, and parasitic infections. It is a structurally well-characterized enzyme that also deacetylates nonhistone proteins. In Cancer, HDAC8 is a major 'epigenetic player' that is linked to deregulated expression or interaction with transcription factors critical to tumorigenesis. In the Parasite Schistosoma mansoni and in viral infections, HDAC8 is a novel target to subdue Infection. The current challenge remains in the development of potent selective inhibitors that would specifically target HDAC8 with fewer adverse effects compared with pan-HDAC inhibitors. Here, we review HDAC8 as a drug target and discuss inhibitors with respect to their structural features and therapeutic interventions.

Keywords
Cornelia de Lange syndrome; HDAC8; X-ray crystallography; cancer; histone deacetylases; schistosoma.