Epigenetic protein families: a new frontier for drug discovery

Abstract

Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. At the molecular level, epigenetic regulation involves hierarchical covalent modification of DNA and the proteins that package DNA, such as histones. Here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These protein families are emerging as druggable classes of enzymes and druggable classes of protein-protein interaction domains. In this article, we discuss the known links with disease, basic molecular mechanisms of action and recent progress in the pharmacological modulation of each class of proteins.

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

“…Inhibition of histone methyltransferases is a promising new avenue for therapeutic discovery 1,3 , and potent, selective and cell permeable reagents are urgently needed to link pharmacological inhibition of specific PMTs with desirable phenotypes. We show here that remodelling of the DOT1L cofactor pocket allows competition by chemical inhibitors with physico-chemical properties distinct from and more drug-like than those of SAM.…”

“…Mutation or misregulation of PMTs is linked to many diseases, especially cancer, and there is strong interest in this family of proteins as potential drug targets [1][2][3] . Targeting the common S-adenosylmethionine (SAM) cofactor-binding site of PMTs is an attractive strategy for this family, analogous to targeting the ATP-binding site of protein kinases 4,5 .…”

“…Targeting the common S-adenosylmethionine (SAM) cofactor-binding site of PMTs is an attractive strategy for this family, analogous to targeting the ATP-binding site of protein kinases 4,5 . There are 60 PMTs encoded in the human genome, including 51 lysine methyltransferases (PKMTs) and 9 protein arginine methyltransferases (PRMTs) 1 . Most PKMTs contain a conserved SET domain, with the exception of DOT1L, which has a protein fold that more closely resembles PRMTs 6 .…”

DOT1L Inhibitor EPZ-5676 Displays Synergistic Antiproliferative Activity in Combination with Standard of Care Drugs and Hypomethylating Agents inMLL-Rearranged Leukemia Cells

“…There is considerable evidence that epigenetic regulation of gene transcription results from the combinatorial effects of distinct covalent modifications of chromatin components, including histone methylation, histone acetylation, other covalent histone modifications, and direct methylation of chromosomal DNA at CpG islands by the DNMTs (Kouzarides, 2007;Arrowsmith et al, 2012). With this in mind, we tested the impact of combining the HMT inhibitor EPZ-5676 with compounds that affect their pharmacology by inhibition of other chromatin regulators, such as histone deacetylases (HDACs), histone demethylases, acetyl-lysine reader domains (bromodomains), and DNMTs.…”

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

“…Among the deregulated epigenetic mechanisms, in addition to DNA methylation and histone (H) de-acetylation, alterations in histone H3 lysine (K)-specific methylation are involved in promoting the aberrant gene expression or 'transcriptome' in AML cells, which includes the deregulated expression of oncogenes and tumor suppressor genes (5,6). While the levels H3K27 trimethylation (3Me) and H3K9Me3 are among the repressive chromatin marks, H3K4Me3 is a permissive histone modification that promotes gene transcription (3,6). LSD1 (KDM1A) is an FAD-dependent histone demethylase, with homology to amine oxidases, which demethylates di-and mono-methylated K4 on histone H3, reducing the permissive H3K4Me3 (7,8).…”