title: Inhibitors of enzymes catalyzing modifications to histone lysine residues: structure, function and activity.
abstract: Gene expression is partly controlled by epigenetic mechanisms including histone-modifying enzymes. Some diseases are caused by changes in gene expression that can be mitigated by inhibiting histone-modifying enzymes. This review covers the enzyme inhibitors targeting histone lysine modifications. We summarize the enzymatic mechanisms of histone lysine acetylation, deacetylation, methylation and demethylation and discuss the biochemical roles of these modifications in gene expression and in disease. We discuss inhibitors of lysine acetylation, deacetylation, methylation and demethylation defining their structure-activity relationships and their potential mechanisms. We show that there are potentially indiscriminant off-target effects on gene expression even with the use of selective epigenetic enzyme inhibitors.
authors.affiliation: Faculty of Health Sciences, College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.|Pharmaceutical Analysis Laboratory, College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Lillico
authors.affiliation: Faculty of Health Sciences, College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.|Pharmaceutical Analysis Laboratory, College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stesco
authors.affiliation: Faculty of Health Sciences, College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.|Joint Laboratory of Biological Psychiatry Between Shantou University Medical College and College of Medicine, University of Manitoba, Winnipeg, MB, Canada.|Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB, Canada.|Department of Rehabilitation Medicine, Health Sciences Centre (HSC), Winnipeg, MB, Canada.
authors.forename: Tina
authors.initials: T
authors.lastname: Khorshid Amhad
authors.affiliation: Joint Laboratory of Biological Psychiatry Between Shantou University Medical College and College of Medicine, University of Manitoba, Winnipeg, MB, Canada.|Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB, Canada.|Department of Rehabilitation Medicine, Health Sciences Centre (HSC), Winnipeg, MB, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cortes
authors.affiliation: Faculty of Health Sciences, College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.|Joint Laboratory of Biological Psychiatry Between Shantou University Medical College and College of Medicine, University of Manitoba, Winnipeg, MB, Canada.|Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB, Canada.|Department of Rehabilitation Medicine, Health Sciences Centre (HSC), Winnipeg, MB, Canada.
authors.forename: Mike P
authors.initials: MP
authors.lastname: Namaka
authors.affiliation: Faculty of Health Sciences, College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.|Pharmaceutical Analysis Laboratory, College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Lakowski
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D056466:Histone Demethylases; D008239:Lysine
keywords: DOT1L; G9a; HDAC inhibitor; LSD1; epigenetics; histone; lysine acetyltransferase inhibitor; lysine demethylase inhibitor; lysine methyltransferase inhibitor; structure–activity relationship