product name P5091 (P005091)
Description: P5091(P005091) is a selective and potent inhibitor of ubiquitin-specific protease 7 (USP7) with EC50 of 4.2 μM and the closely related USP47. P005091 accelerated the degradation of HDM2, while analogs of the compound induced dose- and time-dependent increases in the protein levels of p53 and p21. In addition, P005091 induced apoptosis in numerous cancer cell lines, including both p53+/+ and p53-mutant cancer cell lines.
References: Cancer Cell. 2012 Sep 11;22(3):345-58.
348.22
Formula
C12H7Cl2NO3S2
CAS No.
882257-11-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 28 mg/mL (80.4 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
4% DMSO+30% PEG 400+ddH2O: 5mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19415009
| In Vitro |
In vitro activity: P5091 is a trisubstituted thiophene with dichlorophenylthio, nitro, and acetyl substituents mediating anti-USP7 activity. P5091 exhibits potent, specific, and selective deubiquitylating activity against USP7. In contrast, P5091 does not inhibit other DUBs or other families of cysteine proteases tested (EC50 > 100 mM). P5091 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 P5091. Moreover, P5091 inhibits USP7- but not USP2- or USP8-mediated cleavage of poly K48-linked ubiquitin chains. USP7 inhibition by P5091 induces HDM2 polyubiquitylation and accelerates degradation of HDM2. P5091 inhibits USP7 deubiquitylating activity, without blocking proteasome activity in MM Cells. P5091 inhibits growth in MM cells and overcomes bortezomib-resistance. P5091 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). P5091 overcomes bone marrow stromal cell-induced growth of MM Cells. P5091 decreased HDM2 and HDMX, as well as upregulated p53 and p21 levels. Overall, P5091-induced cytotoxicity is mediated in part via HDM2-p21 signaling axis and although p53 is upregulated in response to P5091 treatment, the cytotoxic activity of P5091 is not dependent on p53. Kinase Assay: Cell Assay: P005091 exhibits growth inhibition with GI50 value of 1.82 μM in HL-60(TB) cell line and exhibits broad growth inhibition. In HCT-116 cells, P005091 shows cytotoxic activity with EC50 value of 9.21 μM. |
|---|---|
| In Vivo | In animal tumor model studies, P5091 is well tolerated, inhibits tumor growth, and prolongs survival. Combining P5091 with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic anti-MM activity. |
| Animal model | Severe combined immunodeficient (SCID) mice inoculated subcutaneously with human multiple myeloma tumor cells. |
| Formulation & Dosage | 10 mg/kg; injected intravenously |
| References | Cancer Cell. 2012 Sep 11;22(3):345-58. |
