Inhibition of human histone lysine methyltransferases by a redox-labile S-adenosyl-L-homocysteine analog

Methylation of lysine residues in histones by histone lysine methyltransferases is important for epigenetic gene regulation in humans. Histone lysine methyltransferases use S-adenosyl-L-methionine (SAM) as a co-substrate, producing the methylated lysine product and S-adenosyl-L-homocysteine (SAH) by-product. Inhibition of this class of epigenetic enzymes has potential for treatment of human diseases, including cancer. Here, we designed and developed a redox-labile S-adenosyl-L-homocysteine analog (SS-SAH) possessing a disulfide bond as a reversible inhibitor of biomedically important histone lysine methyltransferases GLP, G9a and SETD8. Combined enzyme assays, docking studies and molecular dynamics simulations provide insight into inhibition and binding mode of the redox-labile SS-SAH, and demonstrate that the inhibitory activity of SS-SAH could be deactivated by cleavage of the disulfide bond upon the addition of a reductive agent. Overall, this work highlights a utility of unique redox-labile inhibitors of epigenetic enzymes.