GSK503

GSK503 is a potent and specific inhibitor of EZH2 methyltransferase with K_i^app values of 3 to 27 nM. IC50 & Target:Ki: 3 to 27 nM (EZH2)^[1] In Vitro:GSK503 inhibits the methyltransferase activity of wild type and mutant EZH2 with similar potency (K_i^app=3-27 nM) and is structurally related to GSK126 and GSK343. GSK503 is >200 fold selective over EZH1 (K_i^app=636 nM) and >4000 fold selective over other histone methyltransferases^[1]. In Vivo:In a melanoma mouse model, conditional EZH2 ablation as much as treatment with the GSK503 stabilizes the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology^[2]. GSK503 displays favorable pharmacokinetics in mice. GSK503, but not vehicle, prevents the formation of germinal center after SRBC or NP-KLH immunization, phenocopying the Ezh2 null phenotype. GSK503 treatment leads to reduced numbers of GC B-cells by flow cytometry, reduces number and volume of GCs by immunohistochemistry, and impairs formation high affinity antibodies^[1].