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

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

来源：ACS Medicinal Chemistry Letters, 2015, 6(6): 695-700.

DOI：10.1021/acsmedchemlett.5b00124

• Epigenetics
• SMYD2
• H3K36
• p53
• methyltransferase
• lysine

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.

• 出版日期2015-6