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Review
. 2016 Jun 17;9(1):49.
doi: 10.1186/s13045-016-0279-9.

Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives

Yongcheng Song  1   2 , Fangrui Wu  3 , Jingyu Wu  3
Affiliations
Review

Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives

Yongcheng Song et al. J Hematol Oncol. .

Abstract

Post-translational methylation of histone lysine or arginine residues plays important roles in gene regulation and other physiological processes VSports手机版. Aberrant histone methylation caused by a gene mutation, translocation, or overexpression can often lead to initiation of a disease such as cancer. Small molecule inhibitors of such histone modifying enzymes that correct the abnormal methylation could be used as novel therapeutics for these diseases, or as chemical probes for investigation of epigenetics. Discovery and development of histone methylation modulators are in an early stage and undergo a rapid expansion in the past few years. A number of highly potent and selective compounds have been reported, together with extensive preclinical studies of their biological activity. Several compounds have been in clinical trials for safety, pharmacokinetics, and efficacy, targeting several types of cancer. This review summarizes the biochemistry, structures, and biology of cancer-relevant histone methylation modifying enzymes, small molecule inhibitors and their preclinical and clinical antitumor activities. Perspectives for targeting histone methylation for cancer therapy are also discussed. .

Keywords: Cancer therapeutics; Enzyme inhibitor; Histone demethylase; Histone lysine methyltransferase; Histone methylation; Protein arginine methyltransferase. V体育安卓版.

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Figures

Fig. 1
Fig. 1
Mechanism and structures of histone methyltransferases (HMT). a Mechanism of catalysis for HMTs. Upon binding to a HMT, the histone lysine NH2 group undergoes a nucleophilic attack to the methyl group of SAM, producing a methylated lysine and SAH; b The overall structure of DOT1L-SAM complex (PDB: 1NW3) and the close-up view of its active site; c The overall structure of G9a-SAH complex (PDB: 3K5K) and the close-up view of its active site. SAM/SAH are shown as tube models with their C atoms in green
Fig. 2
Fig. 2
Mechanisms and structures of histone lysine demethylases (KDM). a Mechanism of catalysis for FAD dependent KDM1 proteins (including LSD1 and 2); b The active site of LSD1 in complex with FAD and a histone H3 peptide (PDB: 2V1D). LSD1 is shown as a 50 % transparent electrostatic surface. The peptide is shown as a wire model (C atoms in green), with the K4M residue highlighted as a tube model; c Mechanism of catalysis for JmjC domain KDMs; d The active site of PHF8 in complex with Fe2+ (cyan sphere), an α-KG analog (brown) and a histone H3 peptide (green) (PDB: 3KV4)
Fig. 3
Fig. 3
Histone H3 and H4 lysine substrate-specificity of HMTs and KDMs
Fig. 4
Fig. 4
Functions of wild-type MLL, LSD1 and onco-MLL fusion proteins. a MLL methylates H3K4 and initiates RNA polymerase II (Pol II) mediated gene transcription, while LSD1 removes the methyl group from H3K4me1 and 2 and keeps a balanced H3K4 methylation; b The onco-MLL protein complex involving AF4, AF9, AF10, or ENL can recruit DOT1L, which methylates H3K79 and causes overexpression of leukemia-relevant genes
Fig. 5
Fig. 5
Structures and activities of representative DOT1L inhibitors
Fig. 6
Fig. 6
Structures and activities of representative LSD1 inhibitors
Fig. 7
Fig. 7
Structure and activity of a compound that disrupts MLL:WDR5 interactions and thereby inhibits MLL indirectly
Fig. 8
Fig. 8
Structures and activities of representative EZH2 inhibitors
Fig. 9
Fig. 9
Mechanisms and inhibitors of IDH. a Mechanism of catalysis for the wild-type IDH. b Mechanism of catalysis for mutant IDHs. c Structures and activities of representative inhibitors of mutant IDH
Fig. 10
Fig. 10
Structures and activities of representative inhibitors of a G9a/GLP; b SMYD2; c PRMTs; and d KDM6
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