Silmitasertib (CX-4945)

製品コードS2248 バッチS224801

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C19H12ClN3O2
分子量 349.77 CAS No. 1009820-21-6
Solubility (25°C)* 体外 DMSO 70 mg/mL (200.13 mM)
Water Insoluble
Ethanol Insoluble
* <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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 Silmitasertib (CX-4945) is a potent and selective inhibitor of CK2 (casein kinase 2) with IC50 of 1 nM in a cell-free assay, less potent to Flt3, Pim1 and CDK1 (inactive in cell-based assay). Silmitasertib induces autophagy and promotes apoptosis. Phase 1/2.
in vitro

CX-4945 is selective for CK2, as it only inhibits 7 of the 238 kinases by more than 90% at concentration of 0.5 μM, which is 500-fold greater than the IC50 of CK2. Although in cell-free systems CX-4945 inhibits FLT3, PIM1, and CDK1 with IC50 of 35 nM, 46 nM, and 56 nM, respectively, CX-4945 treatment at 10 μM is inactive against FLT3, PIM1, and CDK1 in cell-based functional assays. CX-4945 exhibits a broad spectrum of antiproliferative activity, and the breast cancer cell lines displays the widest range of sensitivity to CX-4945 with EC50 of 1.71-20.01 μM. The antiproliferative activity of CX-4945 correlates with CK2α mRNA and protein levels but not the CK2α' catalytic subunit, the regulatory CK2β subunit, and the PI3K/Akt or PTEN mutational status. CX-4945 inhibits PI3K/Akt signaling by directly blocking the phosphorylation of Akt at Serine 129 by CK2 rather than through activation of PTEN. CX-4945 treatment causes reduced phosphorylation of p21 (T145), increased levels of total p21 and p27, and induction of caspase 3/7 activity. CX-4945 treatment induces a G2/M cell-cycle arrest in BT-474 cells and a G1 arrest in BxPC-3 cells. CX-4945 inhibits HUVEC proliferation, migration, and tube formation with IC50 of 5.5 μM, 2 μM, and 4 μM, respectively. Under hypoxic conditions in BT-474 and BxPC-3 cells, CX-4945 treatment prevents downregulation of p53 and pVHL and reduces activation of HIF-1α transcription. [1] CX-4945 potently inhibits endogenous intracellular CK2 activity with IC50 of 0.1 μM in Jurkat cells. [2]
in vivo

Oral administration of CX-4945 at 25 mg/kg or 75 mg/kg twice daily displays potent antitumor activity in the BT-474 model, with TGI of 88% and 97%, respectively, and 2 of 9 animals in each group showing more than 50% reduction in tumor size compared with the initial tumor volume. In the BxPC-3 model, CX-4945 treatment at 75 mg/kg twice daily shows 93% TGI with 3 animals having no evidence of tumor remaining at the end of the treatment period. [1] In PC3 xenograft model, administration of CX-4945 at 25 mg/kg, 50 mg/kg, or 75 mg/kg causes tumor growth inhibition with TGI of 19%, 40%, and 86%, respectively. [2]
特徴 First clinical inhibitor of CK2.

プロトコル(参考用のみ)

キナーゼアッセイ CK2 Kinase Assay
CX-4945 is added at a volume of 10 μL to a reaction mixture comprising 10 μL of assay dilution buffer (ADB; 20 mM MOPS, pH 7.2, 25 mM β-glycerolphosphate, 5 mM EGTA, 1 mM sodium orthovanadate, and 1 mM dithiothreitol), 10 μL of substrate peptide (RRRDDDSDDD, dissolved in ADB at a concentration of 1 mM), 10 μL of recombinant human CK2 (ααββ-holoenzyme, 25 ng dissolved in ADB). Reactions are initiated by the addition of 10 μL of ATP solution (90% 75 mM MgCl2, 75 μM ATP (final ATP concentration=15 μM) dissolved in ADB; 10% [γ-33P]ATP (stock 1 mCi/100 μL; 3000 Ci/mM and maintained for 10 minutes at 30 °C. The reactions are quenched with 100 μL of 0.75% phosphoric acid and then transferred to and filtered through a phosphocellulose filter plate. After washing each well five times with 0.75% phosphoric acid, the plate is dried under vacuum for 5 minutes and, following the addition of 15 μL of scintillation fluid to each well, the residual radioactivity is measured using a Wallac luminescence counter. The IC50 values are derived from eight concentrations of CX-4945 over a range of 0.0001 μM to 1 μM.
細胞アッセイ 細胞株 SKBr3, MDA-MB-453, BT-474, ZR-75-1, MDA-MB-231, MDA-MB-468, T47D, MCF 7, Hs578T, MDA-MB-361, UACC-812, et al.
濃度 Dissolved in DMSO, final concentrations ~100 μM
反応時間 4 days
実験の流れ

Cells are seeded at a density of 3,000 cells per well 24 hours prior to treatment, in appropriate media, and then treated with various concentrations of CX-4945. Suspensions cells are seeded and treated on the same day. Following 4 days of incubation, Alamar Blue (20 μL, 10% of volume per well) is added and the cells are further incubated at 37 °C for 4-5 hours. Fluorescence with excitation wavelength at 530-560 nm and emission wavelength at 590 nm is measured.
動物実験 動物モデル Female immunocompromised mice CrTac:Ncr-Foxn1nu injected with BxPC-3 or BT-474 cells
投薬量 25 or 75 mg/kg
投与方法 Oral gavage twice daily

カスタマーフィードバック

Data from [Nat Commun, 2014, 5, 3393]

Data from [Cell Signal, 2014, 26(7), 1567-75]

Data from [Cell Signal, 2014, 26(7), 1567-75]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

CK2 activity is crucial for proper glucagon expression [ Diabetologia, 2024, 10.1007/s00125-024-06128-1] PubMed: 38503901
Rutaecarpine alleviates inflammation and fibrosis by targeting CK2α in diabetic nephropathy [ Biomed Pharmacother, 2024, 180:117499] PubMed: 39353318
Protein kinase CK2α is overexpressed in classical hodgkin lymphoma, regulates key signaling pathways, PD-L1 and may represent a new target for therapy [ Front Immunol, 2024, 15:1393485] PubMed: 38807597
"Phosphoproteomic quantification based on phosphopeptide intensity or occupancy? An evaluation based on casein kinase 2 downstream effects" [ J Proteomics, 2024, 307:105269] PubMed: 39098729
Mitochondrial ALDH2 improves ß-cell survival and function against doxorubicin-induced apoptosis by targeting CK2 signaling [ J Diabetes Investig, 2024, 15(6):684-692] PubMed: 38713732
Sex specific emergence of trisomic Dyrk1a-related skeletal phenotypes in the development of a Down syndrome mouse model [ bioRxiv, 2024, 2024.05.24.595804] PubMed: 38826419
Mcam stabilizes luminal progenitor breast cancer phenotypes via Ck2 control and Src/Akt/Stat3 attenuation [ bioRxiv, 2024, 2023.05.10.540211] PubMed: 38562809
A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors [ Signal Transduct Target Ther, 2023, 8(1):183] PubMed: 37160887
CSNK2B modulates IRF1 binding to functional DNA elements and promotes basal and agonist-induced antiviral signaling [ Nucleic Acids Res, 2023, 51(9):4451-4466] PubMed: 37094077
CSNK2 suppresses autophagy by activating FLN-NHL-containing TRIM proteins [ Autophagy, 2023, 10.1080/15548627.2023.2281128] PubMed: 37938186

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人間や獣医の診断であるか治療的な使用のためにでない。

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