Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2

  • ACS Med Chem Lett. 2015 Apr 29;6(6):695-700. doi: 10.1021/acsmedchemlett.5b00124.
Ramzi F Sweis  1 ,  Zhi Wang  1 ,  Mikkel Algire  1 ,  Cheryl H Arrowsmith  2 ,  Peter J Brown  3 ,  Gary G Chiang  1 ,  Jun Guo  1 ,  Clarissa G Jakob  1 ,  Steven Kennedy  3 ,  Fengling Li  3 ,  David Maag  1 ,  Bailin Shaw  1 ,  Nirupama B Soni  1 ,  Masoud Vedadi  4 ,  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, ON M5G 1L7, Canada ; Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto , Toronto, ON M5G 2M9, Canada.
  • 3. Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
  • 4. Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada ; Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada.
PMID: 26101576 DOI: 10.1021/acsmedchemlett.5b00124
Abstract

A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 Inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.

Keywords
Epigenetics; H3K36; SMYD2; lysine; methyltransferase; p53.
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