2014•ACS Medicinal Chemistry LettersOpen access
Discovery and Development of Potent and Selective Inhibitors of Histone Methyltransferase G9a
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
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Abstract
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.