Home Angiogenesis Bcr-Abl Remmer Degrasyn (WP1130)

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Degrasyn (WP1130) Bcr-Abl Remmer

Cat.nr.: S2243

Degrasyn (WP1130) is een selectieve deubiquitinase (DUB: USP5, UCH-L1, USP9x, USP14 en UCH37) remmer en onderdrukt ook Bcr/Abl, tevens een JAK2-transducer (zonder het 20S proteasoom te beïnvloeden) en activator van transcriptie (STAT). Deze verbinding induceert apoptose en blokkeert autophagy.
Degrasyn (WP1130) Bcr-Abl Remmer Chemical Structure

Chemische structuur

Molecuulgewicht: 384.27

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Kwaliteitscontrole (Quality Control)

Batch: Zuiverheid: 99.97%
99.97

Celkweek, behandeling & werkzame concentratie
(Cell Culture, Treatment & Working Concentration)

Cellijnen Assaytype Concentratie Incubatietijd Formulering Activiteitsbeschrijving PMID
Mino Cytotoxicity assay 72 hrs Cytotoxicity against human Mino cells after 72 hrs by MTT assay, IC50=0.8μM 24457091
MM1 Antitumor assay 24 to 72 hrs Antitumor activity against human MM1 cells after 24 to 72 hrs by MTT assay, IC50=1μM 22036213
MM1S Cytotoxicity assay 72 hrs Cytotoxicity against human MM1S cells after 72 hrs by MTT assay, IC50=1.2μM 24457091
U266 Antitumor assay 24 to 72 hrs Antitumor activity against human U266 cells after 24 to 72 hrs by MTT assay, IC50=1.3μM 22036213
OCI-My4 Antitumor assay 24 to 72 hrs Antitumor activity against human OCI-My4 cells after 24 to 72 hrs by MTT assay, IC50=1.5μM 22036213
A375 Cytotoxicity assay 72 hrs Cytotoxicity against human A375 cells after 72 hrs by MTT assay, IC50=1.7μM 24457091
K562 Cytotoxicity assay 72 hrs Cytotoxicity against human K562 cells after 72 hrs by MTT assay, IC50=2.4μM 24457091
Z138 Function assay 1 hr Inhibition of UCH-L1 in human Z138 cells after 1 hr by immunoblotting analysis, IC50=3μM 23791076
Z138 Function assay 1 hr Inhibition of USP9x in human Z138 cells after 1 hr by immunoblotting analysis, IC50=3μM 23791076
Z138 Function assay 1 hr Inhibition of USP5 in human Z138 cells after 1 hr by immunoblotting analysis, IC50=3μM 23791076
Z138 Function assay 1.25 to 5 uM 4 hrs Inhibition of Usp9x in human Z138 cells using HA-Ub vinyl-sulfone as substrate at 1.25 to 5 uM after 4 hrs by immunoblotting analysis 24457091
Z138 Function assay 1.25 to 5 uM 4 hrs Inhibition of Usp9x in human Z138 cells at 1.25 to 5 uM incubated for 4 hrs by SDS-PAGE and immunoblotting ChEMBL
Z138 Function assay 1.25 to 5 uM 4 hrs Inhibition of Usp9x in human Z138 cells assessed as reduction in Mcl-1 protein level at 1.25 to 5 uM incubated for 4 hrs by SDS-PAGE and immunoblotting ChEMBL
Z138 Function assay 1.25 to 5 uM 4 hrs Inhibition of Usp9x in human Z138 cells at 1.25 to 5 uM incubated for 4 hrs by immunoblotting analysis ChEMBL
Z138 Function assay 1.25 to 5 uM 4 hrs Inhibition of Usp9x in human Z138 cells assessed as reduction in Mcl1 protein levels at 1.25 to 5 uM incubated for 4 hrs by immunoblotting analysis ChEMBL
Klik om meer experimentele gegevens over cellijnen te bekijken

Chemische informatie, opslag en stabiliteit (Chemical Information, Storage & Stability)

Molecuulgewicht 384.27 Formule

C19H18BrN3O

 Opslag (vanaf de datum van ontvangst)
CAS-nr. 856243-80-6 SDF downloaden Opslag van stamoplossingen

Synoniemen N/A Smiles CCCC(C1=CC=CC=C1)NC(=O)C(=CC2=NC(=CC=C2)Br)C#N

Oplosbaarheid (Solubility)

In vitro
Batch:

DMSO : 77 mg/mL (200.37 mM)
(Met vocht verontreinigd DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Ethanol : 50 mg/mL

Water : Insoluble

Molariteitscalculator

Massa Concentratie Volume Molecuulgewicht
Verdunningscalculator Molecuulgewichtcalculator

In vivo
Batch:

In vivo formulatiecalculator (heldere oplossing)

Stap 1: Voer onderstaande informatie in (Aanbevolen: een extra dier om rekening te houden met verlies tijdens het experiment)

mg/kg g μL

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in de sectie oplosbaarheid.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-moedervloeistof: mg geneesmiddel vooropgelost in μL DMSO ( Concentratie moedervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de batch van het geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO moedervloeistof, voeg daarna toeμL PEG300, mengen en verhelderen, daarna toevoegenμL Tween 80, mengen en verhelderen, daarna toevoegen μL ddH2O, mengen en verhelderen.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO moedervloeistof, voeg daarna toe μL Maïsolie, mengen en verhelderen.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysieke methoden zoals vortexen, ultrasoon of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme (Mechanism of Action)

Kenmerken
WP1130 has an advantage in that its activity is not inhibited by a variety of Abl kinase mutations, including T315I.
Targets/IC50/Ki
DUB
(Cell-free assay)
Bcr-Abl
(Cell-free assay)
1.8 μM
In vitro

In addition to inducing rapid down-regulation of Bcr/Abl without affecting Bcr or c-Abl, Degrasyn (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, this compound induces down-regulation of Bcr/Abl within 60 minutes. It 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. This chemical (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. It is more effective in reducing leukemic cell colony formation compared with normal progenitor cells, and effective against primary leukemic cells harboring the T315I mutation. This compound 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, it 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. This chemical (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.

In vivo

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, this compound displays potent inhibitory activity against A375 melanoma tumors established in nude mice.

Referenties