Epigenetics Targets May Enable Discovery of Novel Drugs

The relevance of chemistry to physiology (as well as to every other field of science) is fascinating. The body depends so much on proper chemistry, and a single molecule, atom, or even electron out of place has the potential to do massive harm. Of course, many drugs are created to meet the body's need for appropriate chemistry, but even well-developed and approved drugs have side effects as they cannot truly replicate or maintain the exact chemistry of an ideal biological specimen. The chemical world of physiology is, in my opinion, what makes the study of life both wildly interesting and incredibly complex.

The epigenome is made up of the chemical compounds, such as methyl or acetyl groups, that are attached to the DNA and help to regulate the activity of genes. Abnormal epigenetic changes have an effect on gene transcription in the development of cancer. The epigenome is also associated with "cellular memory" because it carries on heritable gene expression patterns, which are necessary both for cells to give rise only to a specific type of cell and for tumor progression. The reversibility of epigenetic changes brings up the possibility of targeting the epigenome as a means of cancer therapy.

Some cancer cells exhibit an over representation of histone deacetylases (HDACs) which remove acetyl groups from chromatin. Hypoacetylation of histones allows for a condensed chromatin structure and repression of gene transcription. HDAC inhibitors result in hyperacetylation, and this has been shown to cause cell cycle arrest and cancer cell apoptosis.

While many current HDAC inhibitors lack selectivity among the family of HDAC proteins, several have been approved by the FDA. Other drugs currently on trial are aimed at selectively inhibiting single HDAC enzyme isomers. Acetylon's oral ACY-1215 selectively inhibits the extranuclear HDAC6 enzyme and is being tested in combination with other drugs for the treatment of multiple myeloma. These trials have shown "no dose limiting toxicities or severe adverse events" as with nonselective HDAC inhibitor, but the success of epigenetic drug targets is unfortunately diminished by its chemotherapy-like side effects.

Another promising HDAC inhibitor undergoing clinical trials is Syndax's entinostat, which modulates the development of drug tolerance by targeting reversible epigenetic changes in tumors of both metastatic breast cancer and non-small cell lung cancer.

http://www.genengnews.com/insight-and-intelligence/epigenetics-targets-may-enable-discovery-of-novel-drugs/77899928/