Methods and Compositions of Matter for Activating Class I Histone Deacetylases (HDACs) for Treatment of Human Disease

Technology

In neurodegenerative disorders like Alzheimer’s disease and ischemia, neurons abnormally re-enter the cell cycle and undergo DNA damage, which contributes to early neuronal death. Evidence also exists is psychiatric diseases of elevated DNA damage. HDACs are enzymes that remove acetyl groups from histones, leading to chromatin compaction and reduced accessibility of DNA to transcriptional machinery. Class I HDACs—specifically HDAC1, HDAC2, HDAC3, and HDAC8—are critical for repressing cell cycle gene expression, thereby preventing inappropriate cell cycle activation in neurons, as well as for DNA repair. Moreover, increased HDAC activity enhances chromatin stability and facilitates DNA repair, protecting cells from various forms of DNA damage. The disclosed compounds are designed to activate class I HDACs, thereby reducing DNA damage and preventing neuronal cell death.

Problem Addressed

In various neurological disorders and aging, aberrant cell-cycle activity and DNA damage are critical contributors to neuronal cell death. Suppression of DNA damage and stabilization of chromatin architecture represent a key therapeutic strategy for preserving neuronal integrity. The disclosed compounds achieve this by activating class I HDACs, thereby enhancing genomic stability and promoting DNA repair mechanisms within neuronal cells.

Advantages

• Targeted activation of class I HDACs
• Demonstrated efficacy across multiple disease models
• Potential as neuroprotective and restorative therapeutic
• Broad applicability across neurological and psychiatric disorders
• Relevant for the prevention of age-related DNA damage and loss of genomic integrity

Publications

Patnaik, Debasis, Ping-Chieh Pao, Wen-Ning Zhao, et al. “Exifone Is a Potent HDAC1 Activator with Neuroprotective Activity in Human Neuronal Models of Neurodegeneration.” ACS Chemical Neuroscience 12, no. 2 (2021): 271–84, https://doi.org/10.1021/acschemneuro.0c00308.

Pao, Ping-Chieh, Debasis Patnaik, L. Ashley Watson, et al. “HDAC1 Modulates OGG1-Initiated Oxidative DNA Damage Repair in the Aging Brain and Alzheimer's Disease.” Nature Communications 11 (2020): 2484, https://doi.org/10.1038/s41467-020-16361-y.

Kim, Doohon, Christopher L. Frank, Matthew M. Dobbin, et al. “Deregulation of HDAC1 by p25/Cdk5 in Neurotoxicity.” Neuron 60, no. 5 (2008): 803-17, https://doi.org/10.1016/j.neuron.2008.10.015.