3区 · 医学
Article
作者: Maag, David ; Chiang, Gary G. ; Jakob, Clarissa G. ; Kennedy, Steven ; Wang, Zhi ; Sweis, Ramzi F. ; Brown, Peter J. ; Shaw, Bailin ; Algire, Mikkel ; Soni, Nirupama B. ; Arrowsmith, Cheryl H. ; Pappano, William N. ; Vedadi, Masoud ; Guo, Jun ; Li, Fengling
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.