Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives.
Post-translational methylation of histone lysine or arginine residues plays important roles in gene regulation and other physiological processes. 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.
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. ysong@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. ysong@bcm.edu.
Yongcheng
Y
Song
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
Fangrui
F
Wu
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
Jingyu
J
Wu
D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D044127:Epigenesis, Genetic; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy*
D004791:Enzyme Inhibitors; D006657:Histones; D008780:Methyltransferases
Cancer therapeutics; Enzyme inhibitor; Histone demethylase; Histone lysine methyltransferase; Histone methylation; Protein arginine methyltransferase