PinometoSTAT 是有效的DOT1L组蛋白甲基转移酶抑制剂，Ki为 80 pM。它可用于研究多种白血病治疗的实验。

EPZ5676 has been used in trials studying the treatment of Leukemia, Acute Leukemias, Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Acute Lymphocytic Leukemia, among others.

EPZ-5676在最高剂量70.5 mg/kg/天时,使肿瘤完全消退,停止治疗后长达32天不再生长.用EPZ-5676治疗的大鼠没有观察到显著的体重减轻或明显的毒性.连续21天静脉内输注EPZ-5676至MLL重排白血病的异种移植模型,显示抗肿瘤活性,具有剂量依赖性.

EPZ-5676处理导致H3K79甲基化的浓度和时间依赖性减少而不影响其他组蛋白位点的甲基化状态,这导致MLL重排白血病细胞中关键MLL靶基因和选择性凋亡细胞杀伤的抑制。在MV4-11细胞中EPZ-5676减少H3K79二甲基化,细胞IC50为2.6 nM。EPZ-5676抑制MLL-AF4重排细胞系MV4-11的增殖,IC50为9 nM。

EPZ-5676 is dissolved in DMSO. To analyse inhibition of histone methylation in MV4-11 cells following EPZ-5676 treatment, extracted histones (400 ng) are fractionated on a 10-20% Tris HCl gels with Tris-Glycine SDS running buffer under denaturing conditions and transferred to nitrocellulose filters. Filters are cut into strips and incubated for 1 hour in blocking buffer at room temperature (RT) and then incubated overnight at 4°C in blocking buffer. Filters are washed 3 times for 5 minutes with wash buffer (Phosphate buffered saline (PBS) including 0.01% Tween 20 (PBST)) and incubated with infrared tagged secondary antibody at RT for 1 hour. Filters are washed in PBST and reprobed for 1 hour at RT with the appropriate total histone antibody control (mouse anti-histone H3 (1:20,000), CST 3638, or mouse anti-histone H4 (1:10,000), CST 2935). Filters are washed again in PBST and incubated with infrared tagged secondary antibody (IRDye 800Cw donkey-anti-mouse IgG (1:20,000), Li-Cor 926-32212) at RT for 1 hour. After a final ish in PBST, filters are scanned using the Odyssey infared imager (Li-cor). To analyse inhibition of H3K79 methylation in peripheral blood mononuclear cells (PBMCs) from rats dosed with EPZ-5676, 20 μL of PBMC whole cell lysate is fractionated on denaturing gels and analysed by immunoblotting with antibodies to H3K79me2 or total H3. Signal intensities specific for the H3K79me2 antibody and total histone H3 control antibody are quantified using Odyssey software. The H3K79me2 signal intensity is normalized by dividing it by the total histone H3 control signal intensity in the same lane.

1380288-87-8

C30H42N8O3

562.719

EPZ-5676

Ethanol:85 mg/mL (151.1 mM)
DMSO:93 mg/mL (165.3 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years