生物活性

CX-4945 is an ATP-competitive CK2 protein kinase inhibitor with a Ki and an IC50 of 0.38 and 1 nM for recombinant human CK2α, respectively. CX-4945 has broad-spectrum anti-proliferative activity in multiple cancer cell lines. The anti-proliferative activity of CX-4945 against cancer cells correlated with expression levels of the CK2α catalytic subunit. Attenuation of PI3K/Akt signaling by CX-4945 was evidenced by dephosphorylation of Akt on the CK2-specific S129 site and the canonical S473 and T308 regulatory sites. CX-4945 suppresses Akt signaling and inhibits proliferation of HUVEC Cells. CX-4945 causes cell-cycle arrest and selectively induced apoptosis in certain cancer cells. In models of angiogenesis, CX-4945 inhibited human umbilical vein endothelial cell migration, tube formation, and blocked CK2-dependent hypoxia-induced factor 1 alpha (HIF-1α) transcription in cancer cells. Collectively, CX-4945 inhibits pro-angiogenic CK2 signaling in vitro and in vivo. CX-4945 is an inhibitor of Flt-3/Flk-2 and Pim-1.

Kinase activities

Antiproliferativeactivity of CX2-4945

CellAntiproliferative Activity[4]

体外研究

体内研究

激酶实验

In vitro kinase assays[2]

Recombinantkinases were incubated with 50 mM HEPES (pH 7.5), 0.01% BRIJ-35, 10 mM MgCl2,1 mM EGTA, and Ser/Thr peptide. After the 1 hour kinase reaction, 5 μL of a 1:512 dilution of Development Reagentsolution was added. The reaction was developed and terminated, and then thefluorescence ratio was calculated according to the manufacturer’s protocol.

细胞实验

Cellcultures and reagents[5]

The human NSCLC cell lines A549, H1299,Calu-1 and H358 were cultured in RPMI-1640 containing 10% fetal bovine serum,100units/ml penicillin, and 100μg/ml streptomycin at 37˚C in an atmosphere with5% CO2.

Cellsurvival assays

Cells (5×105and 1×106)were seeded into a 60mm dish in triplicate and were treated with the respectiveagents for 72 h. Cells were trypsinized and cell numbers were determined usingan ADAM-MC automatic cell counter according to the manufacturer’s instructions.

动物实验

In vivo subcutaneous human T-ALL mouse model[3]

Mice were housed and bred in a specificpathogen-free animal facility. Eight weeks old nonobese diabetic/severecombined immunodeficient mice were subcutaneously injected in both flanks with10x106MOLT-4.Luc.GFP cells and resuspended in 100μlof phosphate-buffered saline. On day 5, mice were injected with luciferin to assesstumor burden by whole-body bioluminescence imaging and were equally distributedin two groups to receive CX-4945 dissolved in 25mM disodium hydrogen phosphate(Na2HPO4) or vehicle control. Tumor growth was monitoredweekly by bioluminescence and caliper measurements, and mice were weighedfrequently to determine treatment-induced toxicity. For bioluminescenceimaging, mice were anaesthetized, intraperitoneally injected with 150mgD-luciferin per kg body weight and scanned with an IVIS Lumina bioimagingdevice after 15 min. Total flux (photons per second) was calculated using the LivingImage software.

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

例如，已知某工具药用于小鼠的剂量为88 mg/kg , 则用于大鼠的剂量换算方法：将88 mg/kg 乘以小鼠的Km系数（3），再除以大鼠的Km系数（6），得到该药物用于大鼠的等效剂量44 mg/kg。

参考文献

[1] Siddiqui-Jain A, Drygin D, Streiner N, et al. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 2010;70(24):10288-10298.
[2] Kim H, Choi K, Kang H, et al. Identification of a novel function of CX-4945 as a splicing regulator. PLoS One. 2014;9(4):e94978.
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体内溶解度

Clinical Trial Information ( data from http://clinicaltrials.gov )

注：以上所有数据均来自公开文献，并不保证对所有实验均有效，数据仅供参考。

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