Discovery of A‑893, A New Cell-Active Benzoxazinone
Inhibitor of Lysine Methyltransferase SMYD2
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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 (IC<sub>50</sub>: 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