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

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• 作者：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
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：June 11, 2015
• 年：2015
• 卷：6
• 期：6
• 页码：695-700
• 全文大小：364K
• ISSN：1948-5875

文摘

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鈥揳ctivity 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.