97 Other studies have shown that HDAC inhibition Galunisertib enhances learning and memory following neurodegeneration induced by traumatic brain injury,98 and also shows some therapeutic efficacy in rodent models of neurodegenerative conditions, such as Huntington’s disease,99 multiple

sclerosis,100 and Parkinson’s disease.101 One of the downstream effects of HDAC inhibition is upregulation of p21 ,102 a cyclin-dependent kinase inhibitor that appears to play an important protective role against oxidative stress and DNA damage.103 Valproate, a compound utilized for its anticonvulsant and mood-stabilizing properties, also exhibits HDAC activity and has been successfully implemented Inhibitors,research,lifescience,medical as a treatment for epilepsy,104 BD,105 and, less commonly, SZ.106 Like valproate,

it has been discovered that Inhibitors,research,lifescience,medical several drugs have previously unknown epigenetic modifying properties, and the list continues to grow. While such medications are promising, their pleiotropy, transient effects, and nonspecific alterations to the entire epigenome limit them for the time being. A substantial challenge to the field of epigenomics of psychiatric and other diseases involves the identification and verification of inhibitors Inhibitors,research,lifescience,medical for specific histone-modifying enzymes. Once developed, these compounds should provide higher therapeutic efficiency versus the nonspecific therapeutics that are currently in use, such as suberoylanilide hydroxamic acid (SAHA). The development of small, targeted molecules to specific diseasecausing Inhibitors,research,lifescience,medical epimutations may resolve some of these issues but, of course, the molecules themselves must first be identified. Alternately, discovery

of the downstream effects of epimutations in vivo may nominate particular proteins, to which drug interventions can be applied in a more traditional style, using molecules to exert agonistic and antagonistic effects on the protein products of epigenetically misregulated genes. Knowledge of Inhibitors,research,lifescience,medical the three dimensional structures of DNA- and histone-modifying enzymes is mounting and, very through the use of fragmentbased drug design and ligand motif-based libraries,107 virtual screening technologies may soon become a feasible option. In the search for target-specific ligands, highthroughput screening of small organic molecule libraries is a useful tool.108 A recent study utilized a 125 000 small molecule library to screen for specific inhibitors against histone lysine me thyltransf erases (HMTases). The compound discovered was BIX-01294 (diazepinquinazolinamine derivative), an incredibly specific inhibitor of the target enzyme, euchromatic G9a HMTase, that was able to significantly lower promoter-proximal H3K9me2 marks in mouse embryonic stem cells.