中文同义词:
CDK9,CDK8和CDK7抑制剂(LY2857785)
英文同义词:
LY2857785;LY2857785 (LY 2857785;1,4-Cyclohexanediamine, N1-[4-[2-methyl-3-(1-methylethyl)-2H-indazol-5-yl]-2-pyrimidinyl]-N4-(tetrahydro-2H-pyran-4-yl)-, trans-
沸点
671.0±65.0 °C(Predicted)
密度
1.29±0.1 g/cm3(Predicted)
储存条件
Keep in dark place,Sealed in dry,2-8°C
酸度系数(pKa)
10.05±0.40(Predicted)
生物活性
LY2857785 是一种I型可逆的 ATP 竞争性的 CDK9，CDK8 和 CDK7 抑制剂，IC50 分别为 11 nM，16 nM 和 246 nM。
靶点
CDK9
0.011 μM (IC 50 )
CDK8
0.016 μM (IC 50 )
CDK7
0.246 μM (IC 50 )
CDK9
0.011 μM (IC 50 )
CDK8
0.016 μM (IC 50 )
体外研究
LY2857785 shows good selectivity against a panel of 114 protein kinases, with only 5 other protein kinases inhibited with potency (IC 50 ) less than 0.1 μM, and a total of 14 kinases less than 1 μM. At the cellular level, LY2857785 inhibits CTD P-Ser2 and CTD P-Ser5 in U2OS cells at IC 50 s 0.089 (n=13) and 0.042 (n=1) μM, respectively. However, LY2857785 only induces a moderate G 2 -M DNA content increase, from 35% to 55%, with EC 50 0.135 μM. LY2857785 shows potent compound exposure- and time-dependent cell proliferation inhibition in MV-4-11, RPMI8226, and L363 cells. When incubated between 4 to 24 hours, the cell growth inhibition potency reaches a maximal effect at 8 hours with IC 50 s 0.04, 0.2, and 0.5 μM for MV-4-11, RPMI8226, and L363 cells, respectively. LY2857785-induced cancer cell apoptosis is also time dependent, reaching maximal potency at 8 hours with IC 50 0.5 μM in L363 cells.
体内研究
In HCT116 xenograft tumor-bearing mice, LY2857785 demonstrates dose-dependent RNAP II CTD P-Ser2 inhibition potently with TED50 of 4.4 mg/kg and TEC50 of 0.36 μM. LY2857785 also shows significant duration of CTD P-Ser2 inhibition for 3 to 6 hours at TED70 (8 mg/kg) in HCT116 and MV-4-11 nude mice xenograft models. In the nude rat MV-4-11 xenograft model, LY2857785 similarly shows dose-dependent CTD P-Ser2 inhibition for 8 hours at TED70 (7 mg/kg) and TED90 (10 mg/kg). LY2857785 demonstrates the most dramatic tumor regression in the AML MV-4-11 xenograft tumor model either by i.v. bolus in mice or i.v. infusion in rats.
