@article{2c08cdbddb01449fae42e001f5c7c3c8,
title = "Development of a Novel, Small-Molecule Brain-Penetrant Histone Deacetylase Inhibitor That Enhances Spatial Memory Formation in Mice",
abstract = "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.",
author = "Belayet, {Jawad B.} and Sarah Beamish and Mizzanoor Rahaman and Samer Alanani and Virdi, {Rajdeep S.} and Frick, {David N.} and Rahman, {A. F.M.Towheedur} and Ulicki, {Joseph S.} and Sreya Biswas and Arnold, {Leggy A.} and Roni, {M. S.Rashid} and Cheng, {Eric Y.} and Steeber, {Douglas A.} and Frick, {Karyn M.} and Hossain, {M. Mahmun}",
note = "Funding Information: The authors would like to thank Brian Spindler and Dan Murphy for their assistance with compound synthesis, Kayla Simanek, Meredith Frank, and Jessye Hale for assistance with culture experiments, and Sarah M. Philippi for her assistance with memory testing. This project was supported by UWM Research Foundation/Bradley Catalyst grants to M.M.H. and K.M.F., as well as the University of Wisconsin-Milwaukee College of Letters and Science. This project was also funded by the TAP grant (Therapeutic Acceleration Program) Medical College of Wisconsin. K.M.F. and S.B.B. were additionally supported by the National Institutes of Health (R01MH107886, R15GM118304) and the Alzheimer{\textquoteright}s Association (SAGA-17-419092). D.A.S. and S.A. were supported, in part, by an award from the Chancellor{\textquoteright}s Office of the University of Wisconsin-Milwaukee. In addition, this work was supported by grant CHE-1625735 from the National Science Foundation, Division of Chemistry. Funding Information: This project was also funded by the TAP grant (Therapeutic Acceleration Program) Medical College of Wisconsin. K.M.F. and S.B.B. were additionally supported by the National Institutes of Health (R01MH107886, R15GM118304) and the Alzheimer?s Association (SAGA-17-419092). D.A.S. and S.A. were supported, in part, by an award from the Chancellor?s Office of the University of Wisconsin-Milwaukee. In addition, this work was supported by grant CHE-1625735 from the National Science Foundation, Division of Chemistry. Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",
year = "2022",
month = feb,
day = "24",
doi = "10.1021/acs.jmedchem.1c01928",
language = "English",
volume = "65",
pages = "3388--3403",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "4",
}