For research use only. Not Intended for Therapeutic Use!
|IC50:||0.12 uM |
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AZ505 ditrifluoroacetate is a potent and highly selective inhibitor of the oncogenic protein SMYD2(IC50=0.12 uM) with potential anticancer activity, >600 fold than SMYD3(IC50>83.3 uM); DOT1L(IC50>83.3 uM);EZH2(IC50>83.3 uM).
IC50 Value: 0.12 uM 
The kinetics of AZ505 binding to SMYD2 were determined by inhibition kinetic experiments using lter binding assays. Analysis of the double-reciprocal plot of the initial velocities against substrate concentrations indicates that AZ505 binding to SMYD2 is competitive with the peptide substrate and uncompetitive with the cofactor. The inhibition constant for AZ505 was determined to be 0.30 mM using Michaelis-Menten kinetics.
The structure of the ternary complex reveals that a single AZ505 molecule is bound in the peptide binding groove of SMYD2. The cyclohexyl group of AZ505 is positioned in a primaryhydrophobic pocket that is formed at the interface of the core SET and I-SET domains, which is also occupied by residue L369 of the p53 peptide. AZ505 has an IC50 value of 0.12 uM against SMYD2, and has no potency against SMYD3. Comparing the structures of SMYD2 and SMYD3 shows that residue V195 physically restricts access to the primary hydrophobic pocket in SMYD3, which is in agreement with the selectivity profile of AZ505.
. Ferguson AD, et al. Structural basis of substrate methylation and inhibition of SMYD2. Structure. 2011 Sep 7;19(9):1262-73. Abstract Protein lysine methyltransferases are important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine to specific acceptor lysines on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate nonhistone protein substrates, revealing an additional mechanism to regulate cellular physiology. The oncogenic protein SMYD2 represses the functional activities of the tumor suppressor proteins p53 and Rb, making it an attractive drug target. Here we report the discovery of AZ505, a potent and selective inhibitor of SMYD2 that was identified from a high throughput chemical screen. We also present the crystal structures of SMYD2 with p53 substrate and product peptides, and notably, in complex with AZ505. This substrate competitive inhibitor is bound in the peptide binding groove of SMYD2. These results have implications for the development of SMYD2 inhibitors, and indicate the potential for developing novel therapies targeting this target class.