PHA-767491
规格
| Cas Number | 942425-68-5(DMSO) |
| 规格或纯度 | 10mM in DMSO |
| 包装 | 1ml |
产品信息
| 品牌 | 阿拉丁 |
| 浓度 | 10mM in DMSO |
| 溶解性 | Solubility (25°C) In vitro DMSO: 63 mg/mL (199.79 mM); Ethanol: 1 mg/mL (3.17 mM); Water: Insoluble; |
| 简短描述 | CDK9 Selective Inhibitors |
| 英文简短描述 | CDK9 Selective Inhibitors |
| 过滤标签 | Compound libraries |
| 储存温度 | -80℃储存 |
| 运输条件 | 超低温冰袋运输 |
| 生化和生理学机理 | PHA-767491（CAY10572，NMS 1116354）是一种强效的 ATP 竞争性 Cdc7/CDK9 双抑制剂，在无细胞实验中的 IC50 分别为 10 nM 和 34 nM。它对 CDK1/2 和 GSK3-β 的选择性约为 20 倍，对 MK2 和 CDK5 的选择性为 50 倍，对 PLK1 和 CHK2 的选择性为 100 倍。 |
| 描述 |
PHA-767491 hydrochloride 是一种 Cdc7-Dbf4 (DDK)/Cdk9 的双重抑制剂，IC50 值分别为 10 nM和 34 nM。 |
| 英文描述 |
Information PHA-767491 (CAY10572, NMS 1116354) is a potent ATP-competitive dualCdc7/CDK9inhibitor withIC50of 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-fo 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 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 cell lines： Concentrations：Dissolved in DMSO, final concentrations ~ 20 μM Incubation Time：24 or 72 hours Powder Purity:≥99% |