Degrasyn (WP1130) is a cell-permeable tyrphostin compound that acts as a partially selective deubiquitinase (DUB) inhibitor and suppresses JAK-Stat signaling pathway. Reported to cause accumulation of polyubiquitinated p53, JAK2 and Bcr-Abl, and reduce c-Myc and MCL-1 protein levels in several tumor cells and downregulate Stat3 and NF-κB activities (IC50 <1 µM in MCL cells) leading to tumor cell apoptosis (IC50 ~1.2 µM in Z138 cells). Suggested to modify active site cysteine of DUB and inhibit USP5, UCH-L1, USP9x, USP14, and UCH37 activities (≥80% inhibition at 5 µM) without affecting 20S proteasome. Reported to exert stronger antiproliferative and antitumor properties than STAT3 Inhibitor III, WP1066 in xenograft mouse models of CML and melanoma.
|Source||Cancer Res (2010). Figure 1. WP1130|
|Cell Lines||HEK293T cells|
|Incubation Time||2 h|
|Results||WP1130 displayed potent antiproliferative properties against various other tumor cell lines of myeloid and lymphoid origin as well as HEK293T cells|
|Cell lines||CML cells|
|Preparation method||MTT (viability) assay CML cells were seeded in 96-well plates (2*104 cells/well) and WP1130, imatinib mesylate, or dasatinib (0.08-10 µ M) were added in a final volume of 100 µL medium. Plates were incubated at 37°C for 72 hours, after which 20 µL of 3-4,5-dimethylthiazolyl-2-2, 5-diphenyltetrazolium bromide (MTT) reagent (Sigma; stock 5 mg/mL) was added, and the plates were incubated at 37°C for another 2 hours. Cells were lysed with 100 L lysis buffer (20% sodium dodecyl sulfate [SDS] in 50% N, N-dimethylformamide adjusted to pH 4.7 with 80% acetic acid and 1 M hydrochloric acid; final concentration of acetic acid was 2.5% and hydrochloric acid was 2.5%) and incubated for 6 hours. The optical density of each sample at 570 nm was determined with a SPECTRA MAX M2 plate reader (Molecular Devices, Sunnyvale, CA).|
|Concentrations||0.08-10 µ M|
|Incubation time||72 h|
|Animal models||CML tumors and Bcr/Abl-expressing cells in nude mice|
|Formulation||a 0.1-mL suspension of 1:1 dimethylsulfoxide to polyethylene glycol 300|
|Dosages||30 mg/kg every other day for 5 injections|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 60 mg/mL|
Antiviral activity of a small molecule deubiquitinase inhibitor occurs via induction of the unfolded protein response.
Perry JW et al. PLoS Pathog. 2012 Jul;8(7):e1002783. PMID: 22792064.
A novel small molecule deubiquitinase inhibitor blocks Jak2 signaling through Jak2 ubiquitination.
Kapuria V et al. Cell Signal. 2011 Dec;23(12):2076-85. PMID: 21855629.
Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis.
Kapuria V et al. Cancer Res. 2010 Nov 15;70(22):9265-76. PMID: 21045142.
Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells.
Bartholomeusz GA et al. Blood. 2007 Apr 15;109(8):3470-8. PMID: 17202319.
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