PF-06726304 is a potent and selective EZH2 inhibitor with a Ki of 0.7 nM.
PF-06726304 displays potent biochemical and cellular potencies in the Karpas-422 cell line. Upon treatment with PF-06726304 for 7 days, both TNFRSF21 and PRDM1 are upregulated in Karpas-422 cells containing both wild-type and Y641N mutant EZH2 proteins in a dose-dependent manner[1].
PF-06726304 inhibits tumor growth and induces robust modulation of downstream biomarkers in a Karpas-422 in vivo model. Treatment with PF-06726304 is well-tolerated at 200 and 300 mg/kg in mice, with less than 10% body weight loss observed during the course of the experiment. on day 20, PF-06726304 demonstrates tumor stasis and regression at the 200 and 300 mg/kg dose levels, respectively. In addition, tumor growth inhibition is sustained for at least another 3 weeks after the last dose, demonstrating the ability of PF-06726304 to mediate long-term epigenetic reprogramming in cells. PF-06726304 induces approximately 55.5% and 66.4% reduction of the H3K27Me3 level at doses of 200 and 300 mg/kg, respectively. In addition, the PRC2 target genes TNFRSF21 and PRDM1 are both strongly upregulated in both the 200 and 300 mg/kg dosing arms[1].
[1]. Kung PP, et al. Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors. J Med Chem. 2016 Sep 22;59(18):8306-25.