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CX-4945

Cat. No. M1861
CX-4945 Structure
Synonym:

Silmitasertib

Size Price Availability Quantity
10mg USD 140 In stock
50mg USD 380 In stock
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Quality Control
Biological Activity

CX-4945 (Silmitasertib) is the first orally available small molecule inhibitor of protein CK2 in clinical trials for cancer. CX-4945 (Silmitasertib) selectively binds to and inhibits the enzyme casein kinase II (CK2). Protein kinase CK2 (CK2) is involved in a variety of roles essential to the maintenance of cellular homeostasis. CK2 promotes signaling in the Akt pathway and CX-4945 suppresses the phosphorylation of Akt as well as other key downstream mediators of the pathway such as p21. CX-4945 has been reported to show broad spectrum anti-proliferative activity in multiple cancer cell lines. CX-4945 induced apoptosis and caused cell cycle arrest in cancer cells in vitro. CX-4945 exhibited a dose-dependent antitumor activity in a xenograft model of PC3 prostate cancer model and was well tolerated. In vivo time-dependent reduction in the phosphorylation of the biomarker p21 at T145 was observed by immunohistochemistry.

Protocol
Cell Experiment
Cell lines BT-474 (breast) or BxPC-3 (pancreatic) cancer or HUVEC cells
Preparation method A 5 mmol/L stock solution in dimethyl sulfoxide was prepared and stored at - 70 ℃. The drug was diluted directly into growth media immediately prior to use.Various cell lines were seeded at a density of 3,000 cells per well 24 hours prior to treatment, in appropriate media, and then treated with indicated concentrations of CX-4945. Suspensions cells were seeded and treated on the same day.Following 4 days of incubation, Alamar Blue (20 mL, 10% of volume per well) was added and the cells were further incubated at 37 C for 4–5 hours. Fluorescence with excitation wavelength at 530–560 nm and emission wavelength at 590 nm was measured.
Concentrations 0, 0.1, 1.0, 5.0, 10 µM
Incubation time 24 h
Animal Experiment
Animal models Female immunocompromised mice CrTac:Ncr-Foxn1nu (5–7 weeks old) BT474 or BxPC-3 cells Xenografts
Formulation Solubilized in DMSO and diluted with PBS containing 10% dimethylacetamide (Sigma-Aldrich) and 6% Solutol (Sigma-Aldrich).
Dosages twice daily at 25 or 75 mg/kg for 31 and 35 consecutive days
Administration oral gavage
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
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.

Chemical Information
Molecular Weight 349.77
Formula C19H12ClN3O2
CAS Number 1009820-21-6
Purity 99.33%
Solubility DMSO ≥65 mg/mL
Storage at -20°C
Customer Product Validations & Biological Datas
Source Biomed Res Int (2015). Figure 5. CX-4945 (Abmole Bioscience)
Method Wound-Healing Assays
Cell Lines U2OS cells
Concentrations 3 µM
Incubation Time 24 h
Results Both CX-4945 and TDB were able to inhibit cell motility in 24–48 h assayswhen cellswere constantly exposed to them (upper part of the figure).
Rating
Source Biomed Res Int (2015). Figure 4. CX-4945 (Abmole Bioscience)
Method Wound-Healing Assays
Cell Lines U2OS cells
Concentrations 3 µM
Incubation Time 24 h
Results We found that TDB-treated cells were much less prone than vehicle-treated cells to forming spheroids, while CX-4945 was similarly effective than TDB when assessed at 24h but has much weaker effect at longer times after the inhibitor removal.
Rating
Source Biomed Res Int (2015). Figure 3. CX-4945 (Abmole Bioscience)
Method Wound-Healing Assays
Cell Lines U2OS cells
Concentrations 3 µM
Incubation Time 24 h
Results The results, shown in Figure 3, indicate that TDB is much more effective than CX-4945 in preventing clone formation and survival.
Rating
Source Biomed Res Int (2015). Figure 2. CX-4945 (Abmole Bioscience)
Method Western Blot
Cell Lines CEM or U2OS cells
Concentrations 3 µM
Incubation Time 24h, 48h, 72h, 96h
Results The results, shown in Figure 2(b), demonstrated that the phosphorylation of Akt1 Ser129 is similarly reduced by the two inhibitors immediately after treatment, while it remains significantly lower than the control only with TDB in case of inhibitor removal, thus confirming the more permanent blockage of the kinase activity by TDB than by CX-4945.
Rating
Source Biomed Res Int (2015). Figure 1. CX-4945 (Abmole Bioscience)
Method Comparison of CX-4945 and TDB efficacy on cellular CK2 activity.
Cell Lines CEM or U2OS cells
Concentrations 1 µM
Incubation Time 4 h
Results To compare the inhibitory efficacy in cells of the two compounds, CX-4945 and TDB, we analyzed their effects on two cell lines, one deriving from a blood tumor (CEM, T-cell lymphoblastoma) and the other from a solid tumor (U2OS, osteosarcoma). Their efficacy was quite similar in inhibiting cellular CK2.
Rating
Source Growth Factors (2015) . Figure 6.CX-4945 was from AbMole Bioscience (Houston, TX).
Method western blot
Cell Lines fibroblasts from N, T1DM , and T1DM+
Concentrations 10 µM
Incubation Time 72h
Results Although we cannot strictly confirm that all the bands shown in the WB of Figure 6 are direct targets of CK2, our observations suggest that the three cell groups might differ in some regulatory mechanisms which depend on CK2 and can be affected by its blockage.
Rating
Source Growth Factors (2015) . Figure 5.CX-4945 was from AbMole Bioscience (Houston, TX).
Method western blot
Cell Lines fibroblasts from N, T1DM , and T1DM+
Concentrations 10 µM
Incubation Time 72h
Results "we did not find any significant difference of phosphorylation level of a CK2 crucial target, Akt Ser129 among the three cell groups. Also the expression of the total Akt protein was very similar among groups (Figure 5). However, as shown in Figure 5, both CX-4945 and TBB treatment produced a reduction of Sp129-Akt phosphorylation to a level that was very similar among the three groups of cells."
Rating
Source Growth Factors (2015) . Figure 3.CX-4945 was from AbMole Bioscience (Houston, TX).
Method Cell viability assay
Cell Lines fibroblasts from N, T1DM , and T1DM+
Concentrations 10 and 20 µM
Incubation Time 48 h and 72 h
Results The results substantially confirmed those obtained with TBB, showing in addition that the fibroblasts from T1DM+ patients were the most sensitive among the subjects’ groups (Figure 3a), their viability being significantly reduced already at the lower dose (10 mM of CX-4945) within 48 h.
Rating
Source Biochimica et Biophysica Acta (2015) . Figure 4.CX-4945 was purchased from AbMole BioScience (Hong Kong, China.
Method western blot and Immunoprecipitation(IP)
Cell Lines HEK293
Concentrations 2.5µM
Incubation Time 5 h
Results CK2 inhibitor CX-4945 induces the dissociation of a large amount of j-subunit from the eIF3 complex both bound or unbound to the 40S subunits and its shift toward the low-density region of the gradient, where CK2α and CK2β are also detectable (fractions 11–14).
Rating
Source Biochimica et Biophysica Acta (2015) . Figure 3.CX-4945 was purchased from AbMole BioScience (Hong Kong, China.
Method western blot and Immunoprecipitation(IP)
Cell Lines HEK293
Concentrations 2.5µM
Incubation Time 5 h
Results CX-4945 and Q1 strongly reduce the phosphorylation extent of Akt1 Ser129, a specific target of CK2 (about 80% and 65%, respectively), while they do not change the protein-level of CK2α, CK2β and eIF3j(wb).CX-4945 or quinalizarin does not affect the interaction of the kinase with the eIF3 subunits eIF3b and eIF3d, it causes an about 3-fold increase of eIF3j co-immuniprecipitation(IP).
Rating
Source Biochimica et Biophysica Acta (2015) . Figure 1.CX-4945 was purchased from AbMole BioScience (Hong Kong, China.
Method Immunoprecipitation(IP)
Cell Lines HEK293, Hela, LAMA84
Concentrations 0.5µM
Incubation Time 15 min
Results The strong inhibition of the 33P-phosphorylation induced by in vitro addition of the CK2 selective and potent inhibitor CX-4945. The kinase co-immunoprecipitated with eIF3j specifically phosphorylates the subunit as demonstrated by the strong reduction of the eIF3j 33P phosphorylation caused by in vitro addition of the CK2 inhibitor CX-4945.
Rating
Product Citations
References

CK2 inhibitor CX-4945 suppresses DNA repair response triggered by DNA-targeted anticancer drugs and augments efficacy: mechanistic rationale for drug combination therapy.
Siddiqui-Jain et al. Mol Cancer Ther. 2012 Apr;11(4):994-1005. PMID: 22267551.

Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer.
Pierre et al. Mol Cell Biochem. 2011 Oct;356(1-2):37-43. PMID: 21755459.

Structural basis of CX-4945 binding to human protein kinase CK2.
Ferguson et al. FEBS Lett. 2011 Jan 3;585(1):104-10. PMID: 21093442.

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Abmole Inhibitor Catalog 2017




Keywords: CX-4945, Silmitasertib supplier, PKC, inhibitors

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