GSK-503 was designed by performing high-throughput screening for EZH2 methyltransferase inhibiting compounds followed by chemical optimization.In a melanoma mouse model, conditional Ezh2 ablation as much as treatment with the preclinical EZH2 inhibitor GSK503 stabilizes the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology.GSK-503 inhibits the methyltransferase activity of WT and mutant EZH2 with similar potency and is structurally related to GSK-126 and GSK-343. GSK-503 was > 200 fold selective over EZH1 (Kappi=636nM) and > 4000 fold selective over other histone methyltransferases.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO 44 mg/mL|
|Related Histone Methyltransferase Products|
Tazemetostat (EPZ-6438) hydrobromide is a potent, selective and orally available EZH2 inhibitor.
PFI-2 hydrochloride is a potent, highly selective and cell-active inhibitor of the methyltransferase activity of SETD7, with IC50 of 2 nM.
CM-272 is a first-in-class reversible dual small molecule inhibitor against G9a and DNMTs in hematological malignancies.
MI-503 is a potent and selective Menin-MLL inhibitor with IC50 of 14.7 nM.
MI-463 is a highly potent and orally bioavailable small molecule inhibitor of the Menin-MLL interaction, with an IC50 value of 15.3 nM.
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