KDM1 Histone Lysine Demethylases as Targets for Treatments of Oncological and Neurodegenerative Disease

Abstract

Histone methylation and demethylation are important processes associated with the regulation of gene transcription, and alterations in histone methylation status have been linked to a large number of human diseases. Initially thought to be an irreversible process, histone methylation is now known to be reversed by two families of proteins containing over 30 members that act to remove methyl groups from specific lysine residues present in the tails of histone H3 and histone H4. A rapidly growing number of reports have implicated the FAD-dependent lysine specific demethylase (KDM1) family in cancer, and several small-molecule inhibitors are in development for the treatment of cancer. An additional role has emerged for KDM1 in brain function, offering additional opportunities for the development of novel therapeutic strategies in neurodegenerative disease. A decade after the identification of KDM1A as a histone demethylase, the first selective inhibitors have now reached the clinic.

Keywords::

• acute myeloid leukemia
• ORY-1001
• Alzheimer’s disease
• ORY-2001
• SCLC
• GSK2879552
• histone lysine demethylases (KDMs)
• Huntington’s disease
• oncology

Financial & competing interests disclosure

T Maes, CM Crusat, A Ortega, S Lunardi, F Ciceri and C Buesa are employees of Oryzon Genomics S.A. S Lunardi and F Ciceri are supported by Marie Curie Initial Training Network FP7-PEOPLE-2011-ITN, PITN-GA-289880; T Maes and C Buesa are shareholders of Oryzon. TCP Somervaille is supported by Cancer Research UK grant number C5759/A12328. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

T Maes, CM Crusat, A Ortega, S Lunardi, F Ciceri and C Buesa are employees of Oryzon Genomics S.A. S Lunardi and F Ciceri are supported by Marie Curie Initial Training Network FP7-PEOPLE-2011-ITN, PITN-GA-289880; T Maes and C Buesa are shareholders of Oryzon. TCP Somervaille is supported by Cancer Research UK grant number C5759/A12328. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.