Epigenetic compounds have become attractive small molecules for targeting the multifaceted aspects of Alzheimer’s disease (AD). Although AD disproportionately affects women, most of the current literature investigating epigenetic compounds for the treatment of AD do not report sex-specific results. This is remarkable because there is rising evidence that epigenetic compounds intrinsically affect males and females differently. This manuscript explores the sexual dimorphism observed after chronic, low-dose administration of a clinically relevant histone deacetylase inhibitor, chidamide (Tucidinostat), in the 3xTg-AD mouse model. We found that chidamide treatment significantly improves glucose tolerance and increases expression of glucose transporters in the brain of males. We also report a decrease in total tau in chidamide-treated mice. Differentially expressed genes in chidamide-treated mice were much greater in males than females. Genes involved in the neuroinflammatory pathway and amyloid processing pathway were mostly upregulated in chidamide-treated males while downregulated in chidamide-treated females. This work highlights the need for drug discovery projects to consider sex as a biological variable to facilitate translation.

The use of inhibitors of epigenetic modifiers in the treatment of acute myeloid leukemia (AML) has become increasingly appealing due to the highly epigenetic nature of the disease. We evaluated a library of 164 epigenetic compounds in a cohort of 9 heterogeneous AML patients using an ex vivo drug screen. AML blasts were isolated from bone marrow biopsies according to established protocols and treatment response to the epigenetic library was evaluated. We find that 11 histone deacetylase (HDAC) inhibitors, which act upon mechanisms of cell cycle arrest and apoptotic pathways through inhibition of zinc-dependent classes of HDACs, showed efficacy in all patient-derived samples. Other compounds, including bromodomain and extraterminal domain (BET) protein inhibitors, showed efficacy in most samples. Specifically, HDAC inhibitors are already clinically available and can be repurposed for use in AML. Results in this cohort of AML patient-derived samples reveal several epigenetic compounds with high anti-blast activity in all samples, despite the molecular diversity of the disease. These results further enforce the notion that AML is a predominantly epigenetic disease and that similar epigenetic mechanisms may underlie disease development and progression in all patients, despite differences in genetic mutations.