Degrasyn - CAS 856243-80-6
Catalog number:
B0084-307702
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
C23H25ClN2O4S
Molecular Weight:
460.97
COA:
Inquire
Targets:
Deubiquitinase
Description:
Degrasyn, also known as WP1130, is 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 and Hsp90/Hsp70 ratios within the cells. 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. WP1130 may be useful in treating CML. MM1: IC50 = 1 µM (human); U-266: IC50 = 1.3 µM (human); USP9X: IC50 = 3 µM (human); UCH-L1: IC50 = 3 µM (human); USP5: IC50 = 3 µM (human) In vitro: 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; In vivo: 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;
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Purity:
≥ 98.0%
Appearance:
White solid powder
Synonyms:
(E)-3-(6-bromopyridin-2-yl)-2-cyano-N-[(1S)-1-phenylbutyl]prop-2-enamide; 2-cyano-N-(1-phenylbutyl)-3-(6-bromopyridin-2-yl)acrylamide; degrasyn; WP1130; WP1130; 856243-80-6; WP 1130; WP-1130; (S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylbutyl)acrylamide; CHEMBL1923233; (2E)-3-(6-Bromo-2-pyridinyl)-2-cyano-N-[(1S)-1-phenylbutyl]-2-propenamide; WP 1130, WP-1130, 856243-80-6; Degrasyn (WP1130); C19H18BrN3O; MLS006011196; SCHEMBL882501; WP1130 - Adooq Bioscience; QCR-21; SCHEMBL1317674; DTXSID50459281; AOB87145; ABP000853; BDBM50437695; ZINC43129417; CS-0483; AK279688; BC638857; HY-13264; KB-81491; SMR004702965; X7509; W-5800; (2E)-3-(6-bromopyridin-2-yl)-2-cyano-N-[(1S)-1-phenylbutyl]prop-2-enamide
Solubility:
Soluble in DMSO (77 mg/ml at 25 °C), water (< 1 mg/ml at 25 °C), ethanol (50 mg/ml at 25 °C), DMF (~20 mg/ml), and 1: 10 solution of DMF: PBS (pH 7.2) (~0.09 mg/ml).
MSDS:
Inquire
Application:
Downregulate the antiapoptotic proteins Bcr/Abl and Jak2 and to upregulate the proapoptotic proteins MCL-1 and p53; Selective small molecular deubiquitinase (USP5, UCH-L1, USP9x, USP14, and UCH37) inhibitor MM1: IC50 = 1 µM (human); U-266: IC50 = 1.3 µM (human); USP9X: IC50 = 3 µM (human); UCH-L1: IC50 = 3 µM (human); USP5: IC50 = 3 µM (human) In vitro: 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; In vivo: 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;
Quality Standard:
In-house standard
Quantity:
Grams-Kilos
InChIKey:
LIDOPKHSVQTSJY-VMEIHUARSA-N
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
Canonical SMILES:
CCCC(C1=CC=CC=C1)NC(=O)C(=CC2=NC(=CC=C2)Br)C#N
1.Decision for cell fate: deubiquitinating enzymes in cell cycle checkpoint
Key-Hwan Lim • Myoung-Hyun Song • Kwang-Hyun Baek. Cell. Mol. Life Sci. (2016) 73:1439–1455
Most DUBs share similar domains such as Cys and His and these domains are closed to the regulation of deubiquitinating activity. This has indicated an advantage for developing inhibitors targeting multiple DUBs. Several inhibitors targeting not only one specific DUB, but two or more DUBs have been screened and studied. The role of WP1130, as a JAK-STAT-signaling inhibitor, was characterized for its anti-proliferative and apoptotic effect in chronic myeloid leukemia (CML) through down-regulation of the Bcr/Abl protein. A further study identified the ability of WP1130 in that several DUBs, such as USP5, USP9X, USP14, and UCH37, inhibited their deubiquitinating activity through treatment with WP1130 without restriction of the 26S proteasome activity. The observation that the cells form aggresome and undergo apoptosis through treatment with WP1130 has suggested that WP1130 has an effect on the modification of Ub-K63 chains in Bcr/Abl in CML. In addition, apoptosis through down-regulation of the proapoptotic protein Mcl-1 through the inhibition of USP9X through treatment with WP1130 was detected not only in CML but also in several cancers. Similar to WP1130, the small molecule b-AP15 inhibits proteasome-associated DUBs such as UCH37 and USP14 without affecting proteasome activity.
2.Alantolactone induces apoptosis in chronic myelogenous leukemia sensitive or resistant to imatinib through NF-kB inhibition and Bcr/Abl protein deletion
Wei Wei • He Huang • Shan Zhao • Wei Liu. Apoptosis (2013) 18:1060–1070
In this study, proteasome inhibitors, including MG132 and epoxomicin, did not rescue the alantolactone-induced decrease in Bcr/Abl, indicating that the Bcr/Abl degradation induced by alantolactone may be proteasome independent. Similar to our results, several other compounds, including WP1130 and adaphostin, could reduce Bcr/Abl protein levels in a proteasome-independent manner. Additionally, p65 silencing did not reduce the Bcr/Abl protein or affect the alantolactone-induced decrease in Bcr/Abl in K562 cells, indicating that alantolactone-induced Bcr/Abl depletion is independent of its NF-kB inhibition activity. A similar situation was observed with other NF-jB inhibitors. For example, pristimerin, a quinone methide triterpenoid, induced the apoptosis of CML cells through parallel NF-kB inactivation and Bcr/Abl inhibition. Together, our results strongly suggested that alantolactone could selectively induce apoptosis in Bcr/Abl? cells by inhibiting the NF-kB signaling pathway and inducing Bcr/Abl degradation. The mechanism underlying the alantolactone-induced depletion of Bcr/Abl warrants further investigation.
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