Development of a Novel, Small-Molecule Brain-Penetrant Histone Deacetylase Inhibitor That Enhances Spatial Memory Formation in Mice

• Published in: Journal of medicinal chemistry 2022-02, Vol.65 (4), p.3388-3403
• Main Authors: Belayet, Jawad B, Beamish, Sarah, Rahaman, Mizzanoor, Alanani, Samer, Virdi, Rajdeep S, Frick, David N, Rahman, A. F. M. Towheedur, Ulicki, Joseph S, Biswas, Sreya, Arnold, Leggy A, Roni, M. S. Rashid, Cheng, Eric Y, Steeber, Douglas A, Frick, Karyn M, Hossain, M. Mahmun
• Format: Article
• Language: English
• Subjects: Animals; Brain - metabolism; Cell Line, Tumor; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - pharmacokinetics; Histone Deacetylase Inhibitors - pharmacology; Mice; Mice, Inbred BALB C; Spatial Memory - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01928

Histone acetylation is a prominent epigenetic modification linked to the memory loss symptoms associated with neurodegenerative disease. The use of existing histone deacetylase inhibitor (HDACi) drugs for treatment is precluded by their weak blood–brain barrier (BBB) permeability and undesirable toxicity. Here, we address these shortcomings by developing a new class of disulfide-based compounds, inspired by the scaffold of the FDA-approved HDACi romidepsin (FK288). Our findings indicate that our novel compound MJM-1 increases the overall level of histone 3 (H3) acetylation in a prostate cancer cell line. In mice, MJM-1 injected intraperitoneally (i.p.) crossed the BBB and could be detected in the hippocampus, a brain region that mediates memory. Consistent with this finding, we found that the post-training i.p. administration of MJM-1 enhanced hippocampus-dependent spatial memory consolidation in male mice. Therefore, MJM-1 represents a potential lead for further optimization as a therapeutic strategy for ameliorating cognitive deficits in aging and neurodegenerative diseases.