| 名稱 | Degrasyn |
| 描述 | Degrasyn (WP1130) (WP1130), a specific deubiquitinase (DUB: USP5, UCH-L1, USP9x, USP14, and UCH37) inhibitor, also inhibits Bcr/Abl, which is a JAK2 transducer (without affecting 20S proteasome) and activator of transcription (STAT). |
| 細(xì)胞實(shí)驗(yàn) | Cells are treated with increasing concentrations of WP1130 (0.08-10 μM) in 96-well plates. Plates are incubated at 37 °C for 72 hours, after which 20 μL of MTT reagent is added, and the plates are incubated at 37 °C for another 2 hours. Cells are lysed with 100 μL 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 is 2.5% and hydrochloric acid is 2.5%) and incubated for 6 hours. The optical density of each sample at 570 nm is determined with a SPECTRA MAX M2 plate reader.(Only for Reference) |
| 激酶實(shí)驗(yàn) | To determine binding kinetic constants, liver or kidney plasma membranes are incubated with increasing concentrations of [3H]-AVP with or without excess (1 μM) unlabelled AVP to obtain a saturation curve. To investigate whether mozavaptan interacts competitively or noncompetitively, the saturation binding of [3H]-AVP is examined in the absence and presence of mozavaptan at concentrations of 0.3 μM and 1 μM in liver membranes and 3 nM, and 10 nM in kidney membranes. Data on the saturation curve are plotted according to the method of Scatchard and fitted by a regression analysis[1]. |
| 體外活性 | 除了快速下調(diào)Bcr/Abl而不影響B(tài)cr或c-Abl之外，WP1130還調(diào)節(jié)Jak2和c-Myc的穩(wěn)定性，但不影響其他激酶（HER1, HER2, c-Kit, FAK, ERK1, ERK2, Akt, Btk, Src及Src相關(guān)激酶）或轉(zhuǎn)錄因子（野生型p53, STAT1, STAT3, STAT5, c-Jun, NF-κB及Max）。與adaphostin和Trisenox不同，WP1130在60分鐘內(nèi)就能引起B(yǎng)cr/Abl的下調(diào)。WP1130誘導(dǎo)髓系和淋巴系腫瘤細(xì)胞凋亡的效率更高，IC50約為0.5-2.5 μM。與之相比，對(duì)正常CD34+造血前體細(xì)胞、皮膚成纖維細(xì)胞或內(nèi)皮細(xì)胞的IC50約為5-10 μM。WP1130（5 μM）特異性和快速地下調(diào)野生型及T315I突變型Bcr/Abl蛋白，而不影響bcr/abl基因表達(dá)或介入蛋白酶體降解途徑，在慢性髓性白血?。–ML）細(xì)胞中伴隨著凋亡的誘導(dǎo)。WP1130在減少白血病細(xì)胞集落形成方面比對(duì)正常祖細(xì)胞更為有效，并且能有效針對(duì)攜帶T315I突變的原發(fā)性白血病細(xì)胞。WP1130誘導(dǎo)MM-1多發(fā)性骨髓瘤和其他腫瘤細(xì)胞系中c-Myc蛋白的快速蛋白酶體依賴性降解，與腫瘤生長(zhǎng)抑制相關(guān)。與AG490不同，WP1130作為部分選擇性脫泛素化酶（DUB）抑制劑，能引起快速而顯著的polyubiquitinated (K48/K63-linked)蛋白質(zhì)積累于近核聚集體，而不影響蛋白酶體活性。WP1130（5 μM）直接抑制USP9x, USP5, USP14, UCH-L1及UCH37的DUB活性，但不影響UCH-L3，導(dǎo)致抗凋亡蛋白下調(diào)及促凋亡蛋白上調(diào)，如MCL-1和p53。 |
| 體內(nèi)活性 | WP1130的施用抑制了裸鼠體內(nèi)移植的K562腫瘤以及野生型Bcr/Abl和T315I突變型Bcr/Abl表達(dá)的BaF/3細(xì)胞的生長(zhǎng)。[1] 與c-Myc的下調(diào)一致，WP1130在裸鼠體內(nèi)建立的A375黑色素瘤腫瘤中展示了強(qiáng)大的抑制活性。[2] |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | Ethanol : 15 mg/mL (39 mM)
H2O : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 45 mg/mL (117.11 mM), Sonication is recommended.
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| 關(guān)鍵字 | Autophagy | Inhibitor | DUBs | inhibit | Degrasyn | WP-1130 | Deubiquitinase | Apoptosis | WP 1130 | Bcr-Abl |
| 相關(guān)產(chǎn)品 | Guanidine hydrochloride | Naringin | Valproic Acid | L-Glutamic acid | Gefitinib | Hydroxychloroquine | Dextran sulfate sodium salt (MW 4500-5500) | Stavudine | Tributyrin | L-Ascorbic acid | Paeonol | Sodium 4-phenylbutyrate |
| 相關(guān)庫(kù) | 抑制劑庫(kù) | 抗癌活性化合物庫(kù) | 經(jīng)典已知活性庫(kù) | 已知活性化合物庫(kù) | 細(xì)胞周期化合物庫(kù) | 激酶抑制劑庫(kù) | 抗衰老化合物庫(kù) | 泛素化化合物庫(kù) | 神經(jīng)退行性疾病化合物庫(kù) | 酪氨酸激酶分子庫(kù) |