Background:

AZ505 is a potent SET and MYND domain-containing 2 protein (SMYD2) inhibitor that selectively inhibits the enzymatic activity of SMYD2 (IC50: 0.12 μM) over a variety of other protein lysine methyltransferases (IC50 >83.3 μΜ), including SMYD3, DOT1L, EZH2, GLP, G9A and SET7/9 [1].

AZ505 contains three distinct moieties: the benzooxazinone group which interacts with the lysine-binding channel of SMYD2; the cyclohexyl group which interacts with the core SET and I-SET domains of SMYD2; and the dichlorophenethyl group which extends across the peptide binding groove of SMYD2 [1].

The X-ray crystallographic analysis has revealed that AZ505 binds into the peptide binding groove of SMYD2 competing with the peptide substrates [1].

Reference

参考文献:
[1] Ferguson AD, Larsen NA, Howard T, Pollard H, Green I, Grande C, Cheung T, Garcia-Arenas R, Cowen S, Wu J, Godin R, Chen H, Keen N. Structural basis of substrate methylation and inhibition of SMYD2. Structure. 2011 Sep 7;19(9):1262-73. doi: 10.1016/j.str.2011.06.011. Epub 2011 Jul 21.