PHA-767491 hydrochlorideCAS号: 942425-68-5分子式: C12H11N3O.HCl分子量: 249.7描述纯度储存/保存方法可溶性/溶解性靶点In vitro(体外研究)In vivo(体内研究)参考文献
产品描述 | |
描述 |
PHA-767491 is a potent ATP-competitive dual Cdc7/CDK9 inhibitor with IC50 of 10 nM and 34 nM in cell-free assays, respectively.It displays ~20-fold selectivity against CDK1/2 and GSK3-β, 50-fold selectivity against MK2 and CDK5, 100-fold selectivity against PLK1 and CHK2. |
纯度 |
99.96 %
|
储存/保存方法 |
Store at -20℃ for one year(Powder);Store at 2-4℃ for two weeks;Store at -20℃ for six months after dissolution.
|
基本信息 | |
可溶性/溶解性 |
体外:
DMSO 24mg/mL(96.11mM) Water <1mg>Ethanol <1mg> 1%DMSO+30%polyethyleneglycol+1%Tween80 30mg/mL |
生物活性 | |
靶点 |
Cdc7 ,CDK9 ,GSK-3β ,CDK2 ,CDK1
|
In vitro(体外研究) |
PHA-767491 displays approximately 20-fold selectivity for Cdk1, Cdk2 and GSK3-β, 50-fold selectivity for MK2 and Cdk5 and 100-fold selectivity for PLK1 and CHK2. PHA-767491 inhibits cell proliferation in a variety of human cell lines with IC50 of 0.86 μM for SF-268 to 5.87 μM for K562, and significantly induces apoptosis in a p53-independent manner in almost all cell lines in contrast with 5-FU or gemcitabine which only works in a few of cell lines. Unlike current DNA synthesis inhibitors, PHA-767491 treatment at 5 μM blocks the initiation of DNA replication but not replication fork progression, due to specific inhibition of Cdc7 kinase and Mcm2 phosphorylation at the Cdc7-dependent Ser40 site. The up-regulated Mcl-1 levels in ABT-737-resistant OCI-LY1 and SU-DHL-4 cells can be significantly decreased by PHA-767491 treatment at 3 μM possibly due to the inhibition of Cdk9, leading to the restoration of the sensitivity to ABT-737. The direct mitochondrial dependent pro-apoptosis effect of PHA-767491 is also observed when applied at 1 μM in quiescent chronic lymphocytic leukemia (CLL) cells through the similar mechanism with EC50 of 0.34-0.97 μM. While in proliferating CLL cells stimulated by CD154 and interleukin-4, PHA-767491 treatment at 5 μM abolishes DNA synthesis by inhibiting Cdc7 rather than triggering cell death.
|
In vivo(体内研究) |
Administration of PHA-767491 twice a day for 5 days significantly inhibits the growth of HL60 xenograft in a dose-dependent manner with TGI of 50% and 92% at dose of 20 mg/kg and 30 mg/kg, respectively, the effect of which is also marked in A2780, Mx-1, and HCT-116 xenograft models as well as the DMBA-induced mammary carcinomas, and correlates with Cdc7 inhibition and subsequently decreased phosphorylation of Mcm2 at the Cdc7-dependent site Ser40
|
参考文献 | |
参考文献 |
[1] Montagnoli A, et al. Nat Chem Biol, 2008, 4(6), 357-365. [2] Yecies D, et al. Blood, 2010, 115(16), 3304-3313. [3] Natoni A, et al. Mol Cancer Ther, 2011, 10(9), 1624-1634. |
分子结构图