Discovery and Development of Potent and Selective Inhibitors of Histone Methyltransferase G9a
Ramzi F. Sweis(Structural Genomics Consortium), Marina Pliushchev(AbbVie (United States)), Peter J. Brown(Structural Genomics Consortium), Jun Guo(Structural Genomics Consortium), Fengling Li(University of Toronto), David Maag(AbbVie (United States)), Andrew M. Petros(AbbVie (United States)), Nirupama B. Soni(AbbVie (United States)), Chris Tse(Structural Genomics Consortium), Masoud Vedadi(Structural Genomics Consortium), Michael R. Michaelides(University of Toronto), Gary G. Chiang(University of Toronto), William N. Pappano(AbbVie (United States))
Cited by 185Open Access
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.