Discovery and development of potent and selective inhibitors of histone methyltransferase g9a

  • ACS Med Chem Lett. 2014 Jan 2;5(2):205-9. doi: 10.1021/ml400496h.
Ramzi F Sweis  1 ,  Marina Pliushchev  1 ,  Peter J Brown  2 ,  Jun Guo  1 ,  Fengling Li  2 ,  David Maag  1 ,  Andrew M Petros  1 ,  Nirupama B Soni  1 ,  Chris Tse  1 ,  Masoud Vedadi  2 ,  Michael R Michaelides  1 ,  Gary G Chiang  1 ,  William N Pappano  1
Affiliations
  • 1. Discovery Research, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
  • 2. Structural Genomics Consortium, University of Toronto , Toronto, Canada.
PMID: 24900801 DOI: 10.1021/ml400496h
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.

Keywords
A-366; G9a; epigenetics; methylation; methyltransferase.
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