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

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.

• Authors: 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
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 6 Issue 6 Pg. 695-700 (Jun 11 2015) ISSN: 1948-5875 [Print] United States
• PMID: 26101576 (Publication Type: Journal Article)