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

Ramzi F Sweis; Zhi Wang; Mikkel Algire; Cheryl H Arrowsmith; Peter J Brown; Gary G Chiang; Jun Guo; Clarissa G Jakob; Steven Kennedy; Fengling Li; David Maag; Bailin Shaw; Nirupama B Soni; Masoud Vedadi; William N Pappano

doi:10.1021/acsmedchemlett.5b00124

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. eCollection 2015 Jun 11.

Authors

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.

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.