HDAC Program - EnVivo
Histones and DNA are integrated components of chromatin and the quaternary structure of chromatin plays a primary role in determining those genes that are transcribed and those genes that are repressed. One factor that can impact the probability of gene transcription is the acetylation state of the histones. Histone acetyltransferases (HATs) and HDACs are families of enzymes that are critical for regulating the aceylation state in the genome. HATs transfer acetyl groups onto histone, resulting in an open DNA conformation and allowing transcription factors and RNA polymerases greater access to genes thereby increasing the probability of transcription. In contrast, HDACs remove acetyl groups resulting in a decrease in probability of gene transcription. Therefore, inhibiting HDACs results in an increase in the acetylation state of histone and increases in gene transcription.
Both genetic and sporadic CNS diseases display disturbances in gene transcription. Preclinical models of some diseases (including Huntington’s disease, Parkinson’s disease and deficits in learning and memory) have been demonstrated to respond to commercially available, low potency HDACi’s such as butyrate and valproic acid. Based on published data and results derived from our Drosophila models of neurodegenerative disease, EnVivo embarked on the development of small molecule, CNS-penetrant, orally bioavailable HDACi’s in 2005. This effort has culminated in one of the first HDACi’s developed expressly for CNS diseases, EVP-0334.
|
