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CX-4945_Molecular_structure_CAS_1009820-21-6)
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CX-4945

Catalog No. S2248 Name Selleck Chemicals
CAS Number 1009820-21-6 Website http://www.selleckchem.com
M. F. C19H12ClN3O2 Telephone (877) 796-6397
M. W. 349.77048 Fax (832) 582-8590
Purity Email sales@selleckchem.com
Storage -20°C Chembase ID: 73110

SYNONYMS

IUPAC name
5-[(3-chlorophenyl)amino]benzo[c]2,6-naphthyridine-8-carboxylic acid
IUPAC Traditional name
5-[(3-chlorophenyl)amino]benzo[c]2,6-naphthyridine-8-carboxylic acid
Synonyms
CX4945

DATABASE IDS

CAS Number 1009820-21-6

PROPERTIES

Target PKC
Salt Data Free Base
Storage Condition -20°C

DETAILS

Description (English)
Research Area
Description Solid tumours,Multiple myeloma , Giant lymph node hyperplasia
Biological Activity
Description CX-4945 is a potent and selective inhibitor of CK2α and CK2α' with IC50 of 1 nM.
Targets CK2α CK2α'
IC50 1 nM 1 nM [1]
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]
Clinical Trials A Phase I study of CX-4945 in patients with relapsed or refractory multiple myeloma is currently ongoing.
Features First clinical inhibitor of CK2
Combination Therapy
Description CX-4945 suppresses DNA repair response triggered by Gemcitabine and Cisplatin, and thus synergizes with these agents in models of ovarian cancer. [3] Combination of CX-4945 with Erlotinib results in enhanced attenuation of the PI3K-Akt-mTOR pathway, an increase in apoptosis, synergistic killing of cancer cells in vitro, and improved antitumor efficacy in vivo. [4]
Protocol
Kinase Assay [2]
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.
Cell Assay [1]
Cell Lines 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.
Concentrations Dissolved in DMSO, final concentrations ~100 μM
Incubation Time 4 days
Methods 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.
Animal Study [1]
Animal Models Female immunocompromised mice CrTac:Ncr-Foxn1nu injected with BxPC-3 or BT-474 cells
Formulation Dissolved in DMSO, and diluted in PBS
Doses 25 or 75 mg/kg
Administration Oral gavage twice daily
References
[1] Siddiqui-Jain A, et al. Cancer Res, 2010, 70(24), 10288-10298.
[2] Pierre F, et al. J Med Chem, 2011, 54(2), 635-654.
[3] Siddiqui-Jain A, et al. Mol Cancer Ther, 2012, 11(4), 994-1005.
[4] Bliesath J, et al. Cancer Lett, 2012, 322(1), 113-118.