Histone acetylation is a prominent epigenetic modification linked to the memory loss symptoms associated with aging and neurodegenerative disease. Histone acetylation promotes gene transcription, which is required for the formation of long-term memories. Thus, compounds that maintain histone acetylation, called histone deacetylase inhibitors (HDACi), are promising therapeutics to treat memory loss associated with aging and neurodegenerative disease. However, use of existing HDACi for the treatment of central nervous system disorders is precluded by their weak blood-brain barrier permeability and undesirable toxicity. Here, we address these shortcomings by developing a new class of disulfide-based compounds that are inspired by the scaffold of the FDA-approved HDACi FK288. Our findings indicate that our lead compound, MJM-1, increases overall levels of histone 3 (H3) acetylation and displays cytotoxicity against a prostate cancer cell line. We also observed that MJM-1 has a high tolerability profile in mice compared to FK288. Next, we found that when MJM-1 is administered intraperitoneally (i.p.), it rapidly crosses the blood-brain barrier (BBB) and travels to the hippocampus, a critical brain region responsible for memory formation. Consistent with this finding, we demonstrate that post-training i.p. administration of MJM-1 enhances hippocampal-dependent spatial, but not object recognition, memory consolidation in male mice. These findings collectively demonstrate that MJM-1 is a promising HDACi with low systemic toxicity and beneficial effects on memory formation. Thus, MJM-1 represents a potential lead for further optimization as a therapeutic strategy for ameliorating cognitive deficits in aging and neurodegenerative diseases.

Development of a novel, small-molecule brain-penetratnt histone deacetylase inhibitor that enhances spatial memory formation in mice

ACS Spring Meeting 2021

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