New Drugs Offer Stroke Treatment by Changing Activity of DNA
19 Jul, 2007 10:59 am
The discovery of small molecules that act as inhibitors of enzymes, small machines in cells, that are involved in the chemical modification of proteins around which the DNA in cells is wrapped, offers an entirely new way of creating drugs.
Recently, one of the first HDAC inhibitors has now made its way to the marketplace, thus heralding the success of this fascinating approach to finding new cures for human diseases. This molecule known as SAHA or Vorinostat, is being marketed by the Merck company, and is being used to treat several forms of cancer. This proof of therapeutic activity has now started the research stampede to identify other HDAC inhibitors that may find use in treating other forms of cancer and brain diseases.
The Univ. of Illinois at Chicago group led by Prof. Alan Kozikowski and his postdoctoral fellows together with Dr. Brett Langley and associates of the Cornell University-Burke Medical Institute have now reported on the discovery of unique HDACIs that are able to protect brain cells from oxidative stress-induced cell death. These studies clearly demonstrate that in order to achieve the best protection of these brain cells from free radical damage it is crucial to design compounds that are selective for a small number of the known HDAC enzymes. To date 11 different types of these enzymes have been identified, and their studies show that by inhibiting only a few of these enzymes they are able to achieve the best levels of protection of the brain cells.
Inhibitors showing activity for the wrong type of HDACs can themselves result in toxicity/cell death, as for example found when using molecules that are similar to SAHA.
This work is important as it clearly maps out the best way to achieve the protection of brain cells from oxidative stress [as takes place in stroke, the third leading cause of death], and indicates which HDACs are best targeted. In light of these reported studies, the UIC-Cornell group is now planning to test their best inhibitors in animal models of stroke, in which their compounds will be administered to rodents, and the effect on protecting the brain will me measured. From there, if the findings in rodents are promising, the group would move to studies in monkeys.
During the course of this work, the UIC chemists have also identified another unique HDAC inhibitor that shows activity in the treatment of malaria. These studies are being carried out in collaboration with the Walter Reed Army Institute of Research and Georgetown University.
Kozikowski, A., et al, Functional Differences in Epigenetic Modulators-Superiority of Mercaptoacetamide-Based Histone Deacetylase Inhibitors Relative to Hydroxamates in Cortical Neuron Neuroprotection Studies,