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Home > Products > Angiogenesis > Bcr-Abl Inhibitor > Degrasyn (WP1130) 856243-80-6

Degrasyn (WP1130) 856243-80-6

Product Description

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Molecular Weight:

384.27 Degrasyn (WP1130) is a selective deubiquitinase (DUB: USP5, UCH-L1, USP9x, USP14, and UCH37) inhibitor and also suppresses Bcr/Abl, also a JAK2 transducer (without affecting 20S proteasome) and activator of transcription (STAT).


Biological Activity


In addition to inducing rapid down-regulation of Bcr/Abl without
affecting Bcr or c-Abl, WP1130 also regulates the stability of Jak2 and
c-Myc without affecting other kinases (HER1, HER2, c-Kit, FAK, ERK1,
ERK2, Akt, Btk, Src and Src-related kinases) or transcription factors
(wild-type p53, STAT1, STAT3, STAT5, c-Jun, NF-κB, and Max). Unlike
adaphostin and Trisenox, WP1130 induces down-regulation of Bcr/Abl
within 60 minutes. WP1130 is more effective in inducing Apoptosis of
myeloid and lymphoid tumor cells with IC50 of ~0.5-2.5 μM compared with
normal CD34+ hematopoietic precursors, dermal fibroblasts, or
endothelial cells with IC50 of ~5-10 μM.


WP1130 (5 μM) specifically and
rapidly down-regulates both wild-type and T315I mutant Bcr/Abl protein
without affecting bcr/abl gene expression or engaging the proteasomal
degradation pathway in chronic myelogenous leukemia (CML) cells,
accompanied by induction of apoptosis. WP1130 is more effective in
reducing leukemic cell colony formation compared with normal progenitor
cells, and effective against primary leukemic cells harboring the T315I
mutation. WP1130 induces rapid proteasomal-dependent
degradation of c-Myc protein in MM-1 multiple myeloma and Other tumor
cell lines, correlated with tumor growth inhibition.


Unlike AG490, WP1130 acts as a partly selective deubiquitinase (DUB)
inhibitor to induce a rapid and marked accumulation of polyubiquitinated
(K48/K63-linked) Proteins into juxtanuclear aggresomes without
affecting proteasome activity. WP1130 (5 μM) directly inhibits DUB
activity of USP9x, USP5, USP14, UCH-L1, and UCH37, but not UCH-L3,
resulting in downregulation of antiapoptotic and upregulation of
proapoptotic proteins, such as MCL-1 and p53.


Administration of WP1130 inhibits the growth of K562 tumors as well as
both wildtype Bcr/Abl and T315I mutant Bcr/Abl-expressing BaF/3 cells
transplanted into nude mice. Consistent with the
down-regulation of c-Myc, WP1130 displays potent inhibitory activity
against A375 melanoma tumors established in nude mice.


Protocol(Only for Reference)


Cell Assay: [1]

Cell lines BV173, BV173R, K562, and BaF/3
Concentrations Dissolved in DMSO, final concentrations ~10 μM
Incubation Time 72 hours
Method 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.


Animal Study: [1]

Animal Models Swiss Nu/Nu mice transplanted with K562 tumor cells, BaF/3wt cells, or BaF/3/T315I cells
Formulation Formulated in solution of 1:1 dimethylsulfoxide to polyethylene glycol 300
Dosages ~40 mg/kg every other day
Administration Injected intraperitoneally


Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)


Species Baboon Dog Monkey Rabbit Guinea pig Rat Hamster Mouse
Weight (kg) 12 10 3 1.8 0.4 0.15 0.08 0.02
Body Surface Area (m2) 0.6 0.5 0.24 0.15 0.05 0.025 0.02 0.007
Km factor 20 20 12 12 8 6 5 3

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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) × mouse Km(3) = 11.2 mg/kg
rat Km(6)






Chemical Information




Molecular Weight (MW) 384.27
Formula

C19H18BrN3O

CAS No. 856243-80-6

Storage 3 years -20℃Powder
6 months-80℃in solvent (DMSO, water, etc.)
Synonyms



Solubility (25°C) * In vitro DMSO 77 mg/mL (200.37 mM)
Water <1 mg/mL (
Ethanol 18 mg/mL (46.84 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.




Chemical Name (S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylbutyl)acrylamide







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