WP1130

Deubiquitinase (DUB) inhibitor, Cell permeable CAS# 856243-80-6

WP1130

Catalog No. BCC3686----Order now to get a substantial discount!

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Quality Control of WP1130

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Chemical structure

WP1130

3D structure

Chemical Properties of WP1130

Cas No. 856243-80-6 SDF Download SDF
PubChem ID 11222830 Appearance Powder
Formula C19H18BrN3O M.Wt 384.27
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Degrasyn
Solubility DMSO : 100 mg/mL (260.23 mM; Need ultrasonic)
Chemical Name (E)-3-(6-bromopyridin-2-yl)-2-cyano-N-[(1S)-1-phenylbutyl]prop-2-enamide
SMILES CCCC(C1=CC=CC=C1)NC(=O)C(=CC2=NC(=CC=C2)Br)C#N
Standard InChIKey LIDOPKHSVQTSJY-VMEIHUARSA-N
Standard InChI InChI=1S/C19H18BrN3O/c1-2-7-17(14-8-4-3-5-9-14)23-19(24)15(13-21)12-16-10-6-11-18(20)22-16/h3-6,8-12,17H,2,7H2,1H3,(H,23,24)/b15-12+/t17-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of WP1130

DescriptionDegrasyn (WP1130) is a selective inhibitor of deubiquitinase (DUB: USP5, UCH-L1, USP9x, USP14, and UCH37).
TargetsDUBBcr-Abl    
IC50 1.8 μM    

Protocol

Cell experiment [1]:

Cell lines

The human typical MCL cell lines (Mino, DB, Z-138, and JMP-1)

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

48 h; EC50=~1 μM

Applications

Degrasyn (WP1130) had superior inhibitory activity in the JAK/STAT pathway and the antiproliferative effect. These studies showed that cell growth suppression was seen in all three compounds(WP1130, WP1129 and WP1066 for all four cell lines, and the half maximal effective concentration (EC50) of degrasyn was lower than that of the other two compounds in all four MCL cell lines, suggesting that degrasyn is a more effective anti-tumor agent in MCL cells.

Animal experiment [1]:

Animal models

Young SCID mice

Dosage form

20 mg/kg; i.p.

Application

Useing a xenotransplant SCID mouse model of MCL. Degrasyn alone showed modest prolongation of survival compared with vehicle alone (P<0.105). In addition, normal control mice (n = 5) given treatment with degrasyn alone or in combination with bortezomib remained alive and showed no signs of body weight loss.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Pham L V, Tamayo A T, Li C, et al. Degrasyn potentiates the antitumor effects of bortezomib in mantle cell lymphoma cells in vitro and in vivo: therapeutic implications[J]. Molecular cancer therapeutics, 2010, 9(7): 2026-2036.

WP1130 Dilution Calculator

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WP1130 Molarity Calculator

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Preparing Stock Solutions of WP1130

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.6023 mL 13.0117 mL 26.0234 mL 52.0467 mL 65.0584 mL
5 mM 0.5205 mL 2.6023 mL 5.2047 mL 10.4093 mL 13.0117 mL
10 mM 0.2602 mL 1.3012 mL 2.6023 mL 5.2047 mL 6.5058 mL
50 mM 0.052 mL 0.2602 mL 0.5205 mL 1.0409 mL 1.3012 mL
100 mM 0.026 mL 0.1301 mL 0.2602 mL 0.5205 mL 0.6506 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on WP1130

WP1130, also known as degrasyn, is a second-generation tyrphostin derivative initially identified as a Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathway inhibitor that reduces STAT activation stimulated by cytokines (such as IL-6 and IL-3) through the rapid down-regulation of upstream JAK kinases. WP1130 has also been identified as a selective deubiquitinating enzyme (DUB) inhibitor that directly inhibits DUB activity of USP9x, USP5, USP14 and UCH37 leading to rapid accumulation of polyubiquitinated proteins into juxtanuclear aggresomes and tumor cell apoptosis. WP1130-induced apoptosis and anti-proliferation in tumor cells have been implicated in the treatment of chronic myelogenous leukemia (CML), melanoma, glioblastoma and myeloproliferative disorders.

References:
[1]Kapuria V1, Peterson LF, Fang D, Bornmann WG, Talpaz M, Donato NJ. Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis. Cancer Res. 2010 Nov 15;70(22):9265-76. doi: 10.1158/0008-5472.CAN-10-1530. Epub 2010 Nov 2.
[2]Bartholomeusz GA1, Talpaz M, Kapuria V, Kong LY, Wang S, Estrov Z, Priebe W, Wu J, Donato NJ. Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells. Blood. 2007 Apr 15;109(8):3470-8. Epub 2007 Jan 3.

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References on WP1130

WP1130 increases doxorubicin sensitivity in hepatocellular carcinoma cells through usp9x-dependent p53 degradation.[Pubmed:25749422]

Cancer Lett. 2015 Jun 1;361(2):218-25.

Resistance to chemotherapeutic drugs is a major obstacle in hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms are not well understood. Recent evidence suggests that deubiquitinases (DUB) are key regulators in the mechanisms of cell proliferation, apoptosis and chemoresistance. The present study aimed to investigate whether WP1130, which inhibits activity of deubiquitinases, exerts synergistic cytotoxicity with doxorubicin in HCC and the underlying mechanisms. In the study, we found that Huh7, HepG2, and SNU387 HCC cells with p53 expression displayed enhanced response to the combination therapy compared with p53-deficient HCC cells (Hep3B) in the manner of inhibiting cell proliferation. Downregulation of p53 abolished the synergistic cytotoxicity of doxorubicin and WP1130 on HCC cells. Mechanistically, we found that combined treatment with WP1130 suppressed doxorubicin-mediated upregulation of p53 via promoting its ubiquitin-proteasome dependent degradation, whereas knockdown of DUB usp9x abolished this effect. Taken together, these results demonstrate that combined treatment with WP1130 sensitized HCC cells to doxorubicin via usp9x-depedent p53 degradation.

Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells.[Pubmed:17202319]

Blood. 2007 Apr 15;109(8):3470-8.

Imatinib mesylate (Gleevec) is effective therapy against Philadelphia chromosome-positive leukemia, but resistance develops in all phases of the disease. Bcr/Abl point mutations and other alterations reduce the kinase inhibitory activity of imatinib mesylate; thus, agents that target Bcr/Abl through unique mechanisms may be needed. Here we describe the activity of WP1130, a small molecule that specifically and rapidly down-regulates both wild-type and mutant Bcr/Abl protein without affecting bcr/abl gene expression in chronic myelogenous leukemia (CML) cells. Loss of Bcr/Abl protein correlated with the onset of apoptosis and reduced phosphorylation of Bcr/Abl substrates. WP1130 did not affect Hsp90/Hsp70 ratios within the cells and did not require the participation of the proteasomal pathway for loss of Bcr/Abl protein. WP1130 was more effective in reducing leukemic versus normal hematopoietic colony formation and strongly inhibited colony formation of cells derived from patients with T315I mutant Bcr/Abl-expressing CML in blast crisis. WP1130 suppressed the growth of K562 heterotransplanted tumors as well as both wild-type Bcr/Abl and T315I mutant Bcr/Abl-expressing BaF/3 cells transplanted into nude mice. Collectively, our results demonstrate that WP1130 reduces wild-type and T315I mutant Bcr/Abl protein levels in CML cells through a unique mechanism and may be useful in treating CML.

Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis.[Pubmed:21045142]

Cancer Res. 2010 Nov 15;70(22):9265-76.

Recent evidence suggests that several deubiquitinases (DUB) are overexpressed or activated in tumor cells and many contribute to the transformed phenotype. Agents with DUB inhibitory activity may therefore have therapeutic value. In this study, we describe the mechanism of action of WP1130, a small molecule derived from a compound with Janus-activated kinase 2 (JAK2) kinase inhibitory activity. WP1130 induces rapid accumulation of polyubiquitinated (K48/K63-linked) proteins into juxtanuclear aggresomes, without affecting 20S proteasome activity. WP1130 acts as a partly selective DUB inhibitor, directly inhibiting DUB activity of USP9x, USP5, USP14, and UCH37, which are known to regulate survival protein stability and 26S proteasome function. WP1130-mediated inhibition of tumor-activated DUBs results in downregulation of antiapoptotic and upregulation of proapoptotic proteins, such as MCL-1 and p53. Our results show that chemical modification of a previously described JAK2 inhibitor results in the unexpected discovery of a novel DUB inhibitor with a unique antitumor mechanism.

Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy.[Pubmed:26207339]

Autophagy. 2015;11(9):1458-70.

Autophagy represents an intracellular degradation process which is involved in both regular cell homeostasis and disease settings. In recent years, the molecular machinery governing this process has been elucidated. The ULK1 kinase complex consisting of the serine/threonine protein kinase ULK1 and the adapter proteins ATG13, RB1CC1, and ATG101, is centrally involved in the regulation of autophagy initiation. This complex is in turn regulated by the activity of different nutrient- or energy-sensing kinases, including MTOR, AMPK, and AKT. However, next to phosphorylation processes it has been suggested that ubiquitination of ULK1 positively influences ULK1 function. Here we report that the inhibition of deubiquitinases by the compound WP1130 leads to increased ULK1 ubiquitination, the transfer of ULK1 to aggresomes, and the inhibition of ULK1 activity. Additionally, WP1130 can block the autophagic flux. Thus, treatment with WP1130 might represent an efficient tool to inhibit the autophagy-initiating ULK1 complex and autophagy.

Description

Degrasyn (WP1130) is a cell-permeable deubiquitinase (DUB) inhibitor, directly inhibiting DUB activity of USP9x, USP5, USP14, and UCH37. Degrasyn has been shown to downregulate the antiapoptotic proteins Bcr-Abl and JAK2.

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