Effect of HDAC1/2 Inhibitor compound 60 (Cmpd60) on multiple organ systems in aged Mice

In the current work, we performed multiple in silico drug screens using transcriptional profiles of 2837 small molecules testing their ability to mimic known genetic longevity interventions. We identified one compound that was most commonly found to mimic the transcriptional profile of the genetic longevity interventions. This benzamide-based small molecule, termed compound 60 (Cmpd60; aka Merck60 or BRD 692), is a selective histone deacetylase 1 and 2 (HDAC1/2) inhibitor. Here, we used a combination of molecular, phenotypic, and bioinformatic analyses in multiple disease cell models and mouse models for age-related disease to establish if Cmpd60 acts as a geroprotector. Aged mice: Natural aged, approx. 20 months old, male BL6 mice were acquired from Taconic and single housed under a 12:12-hour light-dark cycle in a room set to 23°C (+/- 0.2°C). All animals were fed a regular chow diet. Mice received daily i.p. injections with either Cmpd60 (n=6) or vehicle (n=7) for 14 days total. Body weight was monitored every 5 days to adjust i.p. volumes to body weight. Cmpd60 treated animals received a dose of 22.5 mg/kg with an i.p. volume of 7.5 ml/kg. Cmpd60 was dissolved in 2% DMSO, 49% PEG400, and 49% saline solution (= vehicle) resulting in a 3 mg/ml concentration. APPSWE-1349 mice: The APPSWE-1349 mice62 (BL6 background) were acquired from Taconic. The transgenic mice possess a transgene coding for the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein carrying the Swedish mutation. Animals (~6-7 months old) were single housed under a 12:12-hour light-dark cycle in a room set to 23°C (+/- 0.2°C). All animals were fed a regular chow diet. Mice received daily i.p. injections with either Cmpd60 (n=12) or vehicle (n=12) for 14 days total. Body weight was monitored every 5 days to adjust i.p. volumes to body weight. Cmpd60 treated animals received a dose of 22.5 mg/kg with an i.p. volume of 7.5 ml/kg. Cmpd60 was dissolved in 2% DMSO, 49% PEG400, and 49% saline solution (= vehicle) resulting in a 3 mg/ml concentration.