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P005091 (P5091) is a cell permeable, potent and specific inhibitor of deubiquitylating enzyme USP7 with an EC50 of 4.2 μM, which induces elevated p53 and apoptosis in cancer cell lines. P005091 inhibits the labeling of USP7 with HA-UbVME in a concentration-dependent manner. USP7-mediated cleavage of high molecular weight polyubiquitin chains is inhibited in a dose-dependent manner by P005091. Moreover, P005091 inhibits USP7- but not USP2- or USP8-mediated cleavage of poly K48-linked ubiquitin chains. USP7 inhibition by P005091 induces HDM2 polyubiquitylation and accelerates degradation of HDM2. P005091 inhibits USP7 deubiquitylating activity, without blocking proteasome activity in MM Cells. P005091 inhibits growth in MM cells and overcomes bortezomib-resistance. P005091 induces a dose-dependent decrease in viability of various MM cell lines, including those that are resistant to conventional therapies dexamethasone (Dex) (MM.1R), doxorubicin (Dox-40), or melphalan (LR5) (IC50 range 6-14 μM). P005091-induced cytotoxicity is mediated in part via HDM2-p21 signaling axis and although p53 is upregulated in response to P005091 treatment, the cytotoxic activity of P005091 is not dependent on p53. P005091 induces HDM2 polyubiquitylation and accelerates degradation of HDM2.
P005091 displays antiangiogenic activity in vivo. P005091 is well tolerated, inhibits tumor growth and prolongs survival in animal models of cancer.
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Source | Int J Mol Sci (2017). Figure 3. P5091 |
| Method | cell proliferation assay | |
| Cell Lines | ovarian cancer cell | |
| Concentrations | 50 μM | |
| Incubation Time | 12 and 24 h | |
| Results | At 12 and 24 hours, control cells treated with DMSO propagated healthily, while the growth of P5091 treated HeyA8 and OVCAR-8 cells was remarkably repressed, with some cells exhibiting rounded shapes or even detaching from the culture dish, indicative of cell death |
| Molecular Weight | 348.22 |
| Formula | C12H7Cl2NO3S2 |
| CAS Number | 882257-11-6 |
| Solubility (25°C) | DMSO 24 mg/mL N-Methylpyrrolidone (NMP): 80 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Related Deubiquitinase Products |
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| CMPD-39
CMPD-39 is a selective USP30 inhibitor with an IC50 of 0.02 μM. CMPD-39 increases protein ubiquitination and accelerates mitophagy. |
| FT709
FT709 is a potent and selective USP9X inhibitor, an IC50 of 82 nM. |
| XL177A
XL177A is a highly potent and selective irreversible USP7 inhibitor with an IC50 of 0.34 nM. |
| LDN-91946
LDN-91946 is a potent, selective and uncompetitive ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitor with a Ki app of 2.8 μM. |
| USP5-IN-1
USP5-IN-1, a potent deubiquitinase USP5 inhibitor, binds to the USP5 ZnF-UBD with a KD of 2.8 μM. |
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