PK11007;PK-11007;PK 11007
| 中文名称 | PK11007;PK-11007;PK 11007 |
|---|---|
| 中文同义词 | 5-氯-2-((4-氟苄基)磺酰基)-N-(5-甲基-1,3,4-噻二唑-2-基)嘧啶-4-甲酰胺 |
| 英文名称 | 5-chloro-2-[(4-fluorophenyl)methylsulfonyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidine-4-carboxamide |
| 英文同义词 | 5-chloro-2-[(4-fluorophenyl)methylsulfonyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidine-4-carboxamide;PK11007;PK-11007;PK 11007;5-Chloro-2-[[(4-fluorophenyl)methyl]sulfonyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-pyrimidinecarboxamide;4-Pyrimidinecarboxamide,5-chloro-2-[[(4-fluorophenyl)methyl]sulfonyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)-;5-Chloro-2-((4-fluorobenzyl)sulfonyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)pyrimidine-4-carboxamide;PK11007,inhibit,MDM-2/p53,Reactive Oxygen Species,Inhibitor,PK 11007,PK-11007 |
| CAS号 | 874146-69-7 |
| 分子式 | C15H11ClFN5O3S2 |
| 分子量 | 427.86 |
| EINECS号 | |
| 相关类别 | |
| Mol文件 | 874146-69-7.mol |
| 结构式 |  |
PK11007;PK-11007;PK 11007 性质
| 密度 | 1.610±0.06 g/cm3(Predicted) |
|---|---|
| 储存条件 | 2-8°C |
| 形态 | 固体 |
| 酸度系数(pKa) | 4.18±0.50(Predicted) |
| 颜色 | 白色至米白色 |
PK11007 (0-120 µM; 24 hours; four p53 wild-type cell lines and fours p53 mutant cell lines) treatment results in a large viability reduction in mutant p53 cell lines MKN1 (V143A), HUH-7 (Y220C), NUGC-3 (Y220C), and SW480 (R273H/P309S) at concentrations ranging from 15 to 30 µM. PK11007 induces mainly caspase-independent cell death.
PK11007 (0-60 µM; 3 hours or 6 hours; NUGC-4, NUGC-3, MKN1, HUH-6, and HUH-7 cancer cells) treatment up-regulates protein levels of the p53 target genes p21, MDM2, and PUMA in a mostly concentration-dependent manner in NUGC-3 (p53-Y220C), HUH-7 (p53-Y220C) and MKN1 (p53-V143A) cells, suggesting partial restoration of transcriptional activity to destabilized p53 mutants. PK11007 also increases p53 activity in HUH-6 and NUGC-4 cells, as indicated by the increase of MDM2, PUMA, and p21 protein levels.
PK11007 (15-20 µM; 4.5 hours or 6 hours; MKN1, HUH-7, NUGC-3, HUH-6 cells) treatment increases transcription of p53 target genes in three mutant p53 cell lines after 6-h treatment. PUMA and p21 mRNA levels are up-regulated by a factor of 2 upon treatment of NUGC-3, MKN, and HUH-7 cells, as well as NOXA for the latter two. MDM2 levels are halved in MKN1 and NUGC-3 cells.
PK11007 viability reduction is potentiated by glutathione depletion. To test whether PK11007 also increases ROS levels, NUGC-3, NUGC-4, HUH-6, HUH-7, and MKN1 cells with PK11007 are incubated for 2 h. There are elevated ROS levels in all cell lines after 2 h. In the mutant p53 cells MKN1, HUH-7, and NUGC-3, however, the ROS increase is higher at 60 µM PK11007 than in NUGC-4 and HUH-6 cells, suggesting that the higher PK11007 sensitivity of the mutant p53 cell lines is mediated by a stronger ROS induction. Basal and PK11007-induced ROS levels in MKN1 cells are at least twofold higher than in other cell lines.
PK11007 inhibits cell proliferation, induces apoptosis and alters genes involved in cell death are all consistent with the ability of PK11007 to reactivate mutant p53.
Cell Viability Assay
| Cell Line: | p53 wild-type cell lines (WI-38, HUH-6, NUGC-4, SJSA-1) and p53 mutant cell lines (HUH-7, NUGC-3, SW480, MKN1) |
| Concentration: | 0 μM, 20 μM, 40 μM, 60 µM, 80 µM, 100 µM and 120 µM |
| Incubation Time: | 24 hours |
| Result: | There was a large viability reduction in mutant p53 cell lines MKN1 (V143A), HUH-7 (Y220C), NUGC-3 (Y220C), and SW480 (R273H/P309S) and in p53 WT cell line SJSA-1 at concentrations ranging from 15 to 30 µM. The p53 WT cancer cell lines HUH-6, NUGC-4 and WI-38 were less sensitive with reduced cell viability only at high concentrations of compound (60 and 120 µM). |
Western Blot Analysis
| Cell Line: | NUGC-4, NUGC-3, MKN1, HUH-6, and HUH-7 cancer cells |
| Concentration: | 0 μM, 15 μM, 30 μM, 60 µM |
| Incubation Time: | 3 hours or 6 hours |
| Result: | Up-regulated protein levels of the p53 target genes p21, MDM2, and PUMA in a mostly concentration-dependent manner in NUGC-3 (p53-Y220C), HUH-7 (p53-Y220C) and MKN1 (p53-V143A) cells. Also increased p53 activity in HUH-6 and NUGC-4 cells, as indicated by the increase of MDM2, PUMA, and p21 protein levels. |
RT-PCR
| Cell Line: | MKN1, HUH-7, NUGC-3, HUH-6 cells |
| Concentration: | 15 μM, 20 μM |
| Incubation Time: | 4.5 hours or 6 hours |
| Result: | Increased transcription of p53 target genes in three mutant p53 cell lines after 6-h treatment. PUMA and p21 mRNA levels were up-regulated by a factor of 2 upon treatment of NUGC-3, MKN, and HUH-7 cells, as well as NOXA for the latter two. MDM2 levels were halved in MKN1 and NUGC-3 cells. |