The homologous protein lysine methyltransferases SUV420H1 and SUV420H2 (collectively named SUV4-20) are important regulators of genomic integrity. A-196 is a selective and potent SUV4-20 inhibitor. It inhibited the methyltransferase activity of SUV420H1 and SUV420H2 with IC50 values of 25 ± 5nM and 144 ± 21nM, respectively. A-196 also showed potent binding affinity for adenosine receptors A1 and A2A with Ki values of 0.021μM and 0.028μM, respectively. A-196 binds to SUV420H1 with a Kd value of 74.8 ± 22.7nM. Treatment of human osteosarcoma cell line U2OS with A-196 for 48 hours led to an increase in H4K20me1 level (EC50 = 735nM) and a decrease in both H4K20me2 (EC50 = 262nM) and H4K20me3 (EC50 = 370nM) levels. Also in U2OS cells, treatment with 6μM A-196 resulted in a robust increase in H4K20me1 level in the S phase and a decrease in H4K20me3 level. A-196 at 1 and 10μM inhibited the ability of primary B cells isolated from the spleens of wild-type mice to switch from IgM to IgG1, IgG3 or IgE[1].
作用机制
A-196 inhibits SUV4-20 in a substrate-competitive manner. It binds within the histone H4 peptide-binding groove of the enzyme and is competitive with the histone peptide substrate, but not with the cofactor S-adenosylmethionine. There is strong cooperativity between the binding of A-196 and S-adenosylmethionine to SUV420H1[1].
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