G9a is a histone lysine methyltransferase responsible for the methylation of histone H3 lysine 9. The discovery of A-366 arose from a unique diversity screening hit, which was optimized by incorporation of a propyl-pyrrolidine subunit to occupy the enzyme lysine channel. A-366 is a potent inhibitor of G9a (IC50: 3.3 nM) with greater than 1000-fold selectivity over 21 other methyltransferases.
Authors: Ramzi F Sweis, Marina Pliushchev, Peter J Brown, Jun Guo, Fengling Li, David Maag, Andrew M Petros, Nirupama B Soni, Chris Tse, Masoud Vedadi, Michael R Michaelides, Gary G Chiang, William N Pappano