Targeting Epigenetics – Not Just Drugs for Cancer
Epigenetics is effectively the study of changes in gene function by covalent modifications. Such modifications result in a stably heritable phenotype that does not involve a change in DNA sequence. There are effectively 2 routes by which such covalent changes can be effected; first by methylation of C5 cytosine bases located 5’ to guanosines. This route is referred to as the cytosine methylation code. In addition, the histone component of chromosomes can be covalently modified at the N-terminus, the so-called histone code.
Epigenetic modification has been the focus of a great deal of interest as targets for the development of anti-cancer drugs. Indeed, there has been some great progress in identifying compounds that can interfere with the epigenetic process and potentially with the disease itself. Such epigenetic approaches have unique properties in the search for novel cancer drugs, in that they can modulate properties of tumours that represent major obstacles in treatment that occur as a result of their adaptive properties, such as metastasis and angiogenesis, amongst others.
The major classes of compounds showing promise at the moment are the DNA methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors and aurora kinase inhibitors, representatives of which have been through clinical trial and have been licensed by the FDA. There is a degree of current focus upon the development of 2nd generation drugs targeting the epigenetic process through enzymes that are capable of mediating restricted histone modification.
Although the epigenetic approach has been largely directed at the development of oncology drugs, there is growing interest in their use in other indications. Of particular interest is their use in CNS indications, diabetes and inflammatory disorders. In this issue of Drug Discovery Today Editor’s Choice, we have provided free downloads of some recent significant articles involved with epigenetics, drugs targeted against it and the use of compounds derived from this approach to the treatment of cancer and non-oncology indications. The first of the 3 downloads is: Epigenetic therapies for non-oncology indications by Jonathan D. Best and Nessa Carey and this article deals with the scope of potential epigenetic drugs in the treatment of a wide range of diseases. The authors highlight some of the issues around the development of compounds for these indications, not least the availability of appropriate in vivo models.
Second in the series of our trio of downloads is the article by José L. Medina-Franco and Thomas Caulfield entitled, “Advances in the computational development of DNA methyltransferase inhibitors”. This review highlights the most up-to-date findings on the virtual screening of compounds and how computational approaches can interlink with other discovery efforts in the search for the optimal compound.
Steve Carney was born in Liverpool, England studied Biochemistry at Liverpool University, obtaining a BSc.(Hons). He then read for a PhD on the Biochemistry and Pathology of Connective Tissue Diseases in Manchester University. On completion of his PhD he moved to the Kennedy Institute of Rheumatology, London 1, where he worked with Professor Helen Muir FRS on the biochemistry of experimental Osteoarthritis. Later, he joined Eli Lilly and Co. where he stayed for 15 years and held a number of positions in Biology R&D, initially in Connective Tissue, but latterly in Neuroscience. He left Lilly in 2002 to take up his present position as Managing Editor, Drug Discovery Today, at Elsevier. He has authored over 40 peer-reviewed articles, written several book chapters and has held a number of patents.