ACY-775

ACY-775, a novel pyrimidine hydroxyl amide small molecule, is a brain bioavailable, highly potent and isoform-selective inhibitor of HDAC6 with IC50 of 7.5 nM. ACY-738 and ACY-775 exhibit a selectivity of 60–1500 times greater than class I HDACs while inhibiting HDAC6 with low nanomolar potency. When it comes to stimulating mouse exploratory behaviors in unfamiliar but novel environments, ACY-738 and ACY-775 cause dramatic increases in α-tubulin acetylation in the brain, unlike tubastatin A, a reference HDAC6 inhibitor with similar potency and peripheral activity but more limited brain bioavailability. Remarkably, ACY-738 and ACY-775 exhibit antidepressant-like effects in the tail suspension test and social defeat paradigm, similar to other HDAC inhibitors like SAHA and MS-275, despite having no discernible effect on histone acetylation. The central inhibition of HDAC6 is directly responsible for the effects of ACY-738 and ACY-775, as these effects are completely abolished in mice that have a loss of function of HDAC6 that is specific to the neurons. Moreover, a behaviorally inactive dosage of ACY-738 combined with a subactive dose of the selective serotonin reuptake inhibitor citalopram significantly enhances the anti-immobility effect. These findings support the viability of this HDAC isoform as a possible target for the development of antidepressants and validate novel isoform-selective probes for in vivo pharmacological investigations of HDAC6 in the CNS.

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.