Biochem/physiol Actions

GSK503 is a potent and selective histone-lysine N-methyltransferase EZH2 (ENX1, KMT6) inhibitor (IC₅₀/K_i^app = 8/3 nM/EZH2, 27 nM/Y641C, ﹤5 nM/A677G, Y641F/H/N/S EZH2 mutants vs. 633/636 nM/EZH1) with >4,000-fold selectivity over other histone methyltransferases and little potency toward panels of histone acetylases/deacetylases, kinases, GPCR/channels/transporters. GSK503 reduces splenocyte H3K27me3 level and prevents post immunization germinal center (GC) formation (150 mg/kg/day i.p.; mice) with good pharmacokinetics in vivo. GSK503 abrogates the GC hyperplasia phenotype of Ezh2(Y641N) mice and suppresses human DLBCL xenografts tumor growth in mice.