PAOA is a selective histone deacetylase (HDAC) inhibitor with IC50 values of 199 and 69 nM for HDAC1 and HDAC3, respectively.1 It is selective for HDAC1 and HDAC3, having IC50 values greater than 1.59 μM for HDAC2, 4, 5, 7, and 8 in a cell-free enzyme assay. In vitro, PAOA induces histone H3 and H4 hyperacetylation.2 PAOA improves the metabolic deficit exhibited by murine striatal cells isolated from HdhQ111 knock-in mice in a dose-dependent manner and reduces eye neurodegeneration in a D. melanogaster model of Huntington’s disease.1 In vivo, PAOA prevents formation of Huntingtin (Htt) protein aggregates in the brain and reduces the cognitive deficits in the N171-82Q mouse model of Huntington’s disease.3
1.Jia, H., Pallos, J., Jacques, V., et al.Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's diseaseNeurobiol. Dis.46(2)351-361(2012) 2.Mai, A., Perrone, A., Nebbioso, A., et al.Novel uracil-based 2-aminoanilide and 2-aminoanilide-like derivatives: Histone deacetylase inhibition and in-cell activitiesBioorg. Med. Chem. Lett.18(8)2530-2535(2008) 3.Jia, H., Kast, R.J., Steffan, J.S., et al.Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington's disease mice: Implications for the ubiquitin-proteasomal and autophagy systemsHum. Mol. Genet.21(24)5280-5293(2012)