Epigenetic targets and drug discovery: part 1: histone methylation.
Dynamic chromatin structure is modulated by post-translational modifications on histones, such as acetylation, phosphorylation and methylation. Research on histone methylation has become the most flourishing area of epigenetics in the past fourteen years, and a large amount of data has been accumulated regarding its biology and disease implications. Correspondingly, a lot of efforts have been made to develop small molecule compounds that can specifically modulate histone methyltransferases and methylation reader proteins, aiming for potential therapeutic drugs. Here, we summarize recent progress in chemical probe and drug discovery of histone methyltransferases and methylation reader proteins. For each target, we will review their biological/biochemical functions first, and then focus on their disease implications and drug discovery. We can also see that structure-based compound design and optimization plays a critical role in facilitating the development of highly potent and selective chemical probes and inhibitors for these targets.
Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Science, Central China Normal University, Wuhan 430079, PR China; Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
Yanli
Y
Liu
Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Science, Central China Normal University, Wuhan 430079, PR China; Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
Ke
K
Liu
Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
Su
S
Qin
Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
Chao
C
Xu
Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Science, Central China Normal University, Wuhan 430079, PR China; Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address: jr.min@utoronto.ca.
Jinrong
J
Min
D002352:Carrier Proteins / Q000378:metabolism; D055808:Drug Discovery; D044127:Epigenesis, Genetic; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D017434:Protein Structure, Tertiary
D002352:Carrier Proteins; D006657:Histones; D011495:Histone-Lysine N-Methyltransferase
Cancer; Chemical probe; Epigenetics; Histone methylation; Inhibitor