Silmitasertib | CX-4945 | CAS#1009820-21-6 | CK2 inhibitor

MedKoo Cat#: 200843 | Name: CX4945 (Silmitasertib)

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Silmitasertib, also know as CX-4945, is an orally bioavailable small-molecule inhibitor of CK2 with potential antineoplastic activity. CK2 inhibitor CX-4945 selectively binds to and inhibits the enzyme casein kinase II (CK2), which may lead to an inhibition of cellular proliferation. CK2, a protein kinase often overexpressed in a variety of cancer cell types, appears to be correlated with malignant transformation, tumor growth and survival.

Chemical Structure

CX4945 (Silmitasertib)

CAS#1009820-21-6 (free acid)

Theoretical Analysis

MedKoo Cat#: 200843

Name: CX4945 (Silmitasertib)

CAS#: 1009820-21-6 (free acid)

Chemical Formula: C19H12ClN3O2

Exact Mass: 349.0618

Molecular Weight: 349.77

Elemental Analysis: C, 65.24; H, 3.46; Cl, 10.14; N, 12.01; O, 9.15

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,650.00	Ready to ship
1g	USD 4,250.00	Ready to ship
2g	USD 6,450.00	Ready to ship

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Related CAS #

1009820-21-6 (free acid) 1309357-15-0 (sodium)

Synonym

CX4945 CX-4945; CX 4945; Silmitasertib.

IUPAC/Chemical Name

5-((3-chlorophenyl)amino)benzo[c][2,6]naphthyridine-8-carboxylic acid

InChi Key

MUOKSQABCJCOPU-UHFFFAOYSA-N

InChi Code

InChI=1S/C19H12ClN3O2/c20-12-2-1-3-13(9-12)22-18-15-6-7-21-10-16(15)14-5-4-11(19(24)25)8-17(14)23-18/h1-10H,(H,22,23)(H,24,25)

SMILES Code

O=C(C1=CC=C2C(N=C(NC3=CC=CC(Cl)=C3)C4=C2C=NC=C4)=C1)O

Appearance

Yellow solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO (up to 15mg/mL)

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#SSC50506

QC Data

View QC data: current batch, Lot#SSC50506

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Silmitasertib (CX-4945) is a, highly selective and potent CK2 inhibitor, with IC50 values of 1 nM against CK2α and CK2α'.

In vitro activity:

In the present study the effects of the CK2 inhibitor, CX4945 on cisplatin [or cis-diamminedichloroplatinum (II); (DDP)]-resistant A549 cells (A549/DDP) were investigated to elucidate the underlying molecular mechanism. A549/DDP cells were divided into four groups (blank control, CX4945, cisplatin and CX4945+cisplatin). Cisplatin resistance was 5.16-fold greater in A549/DDP cells compared with that in A549 cells, with an optimal cisplatin concentration of 5 µg/ml. Moreover, levels of CK2, dishevelled-2 (DVL2) phosphorylated (p) at Ser143 (p-DVL-2Ser143), and major Wnt-signaling proteins were significantly higher in A549/DDP cells compared with that in A549 cells (P<0.05), with these levels further increased following cisplatin treatment (P<0.05), whereas these levels significantly decreased in A549 cells after cisplatin treatment (P<0.05). Additionally, multidrug-resistance-associated protein 1 and lung resistance protein expression was significantly higher in A549/DDP cells compared with that in A549 cells (P<0.05), with these levels increasing further in A549/DDP (P<0.05) but not A549 cells upon cisplatin treatment (P>0.05). In addition, reduced expression of resistance proteins in A549/DDP cells was accompanied by a decline in the 50% growth inhibition after CX4945 pretreatment. Furthermore, levels of p-DVL-2Ser143 and major Wnt-signaling proteins decreased significantly after treatment of A549/DDP cells with CX4945+cisplatin, whereas DVL-2 and p-DVL-2Thr224 levels remained unchanged. Additionally, significant elevations in apoptosis rates in the CX4945+cisplatin group relative to the control and cisplatin-only groups, was observed (P<0.001). These results suggested that inhibiting Wnt/β-catenin signaling with CX4945, which attenuates levels of drug-resistance-associated proteins and induces apoptosis, might reverse cisplatin resistance in NSCLC. Reference: Oncol Lett. 2019 Oct;18(4):3845-3856. https://pubmed.ncbi.nlm.nih.gov/31579410/

In vivo activity:

This experiment focused on CX-4945-mediated effects during and shortly after therapy. To evaluate the immediate effect of CK2 inhibition (twice daily from d7 to d13) on the proliferation of SEM cells in NSG mice, animals were sacrificed during (d10), immediately after (d13) or 48 h after the last therapeutic dose (d15). To examine tumor cell proliferation and distribution, longitudinal bioluminescence imaging (BLI) of all animals was performed on d7, d10, d13 and d15. No differences in blast distribution (Fig.1a) and proliferation (Fig.1b) were observed between treated and untreated animals Pharmacokinetic experiments were conducted to elucidate in which concentrations CX-4945 was present in serum of treated mice (Fig.1c). During therapy CX-4945 concentrations of 190 ± 150 μM (d10) and 155 ± 88 μM (d13) were measured. CX-4945 levels then declined rapidly: two days after the final CX-4945 application (d15) traces were detectable only in one out of four mice. No traces of CX-4945 were detected in untreated animals. Tumor cell frequency in control animals increased rapidly from 3.3 ± 1.4% (d10) to 18.4 ± 8.5% (d15) while CX-4945-treated mice showed decelerated blast counts (2.7 ± 1.2%, 4.7 ± 1.3%, 9.2 ± 8.5% at d10, d13, d15, respectively). Spleen infiltration of ALL cells was reduced accordingly (Fig.1e;1e; Control: 2.3 ± 3.1% vs CX-4945: 1.1 ± 0.4% at d15).This indicates that even short application periods and a moderate dosis of CX-4945 are sufficient to induce signaling-modulating changes in tumor cells. Reference: BMC Cancer. 2020; 20: 184. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057698/

	Solvent	mg/mL	mM
Solubility
	DMSO	40.0	114.59

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 349.77 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Jin C, Song P, Pang J. The CK2 inhibitor CX4945 reverses cisplatin resistance in the A549/DDP human lung adenocarcinoma cell line. Oncol Lett. 2019 Oct;18(4):3845-3856. doi: 10.3892/ol.2019.10696. Epub 2019 Aug 1. PMID: 31579410; PMCID: PMC6757301. 2. Silva-Pavez E, Villar P, Trigo C, Caamaño E, Niechi I, Pérez P, Muñoz JP, Aguayo F, Burzio VA, Varas-Godoy M, Castro AF, Colombo MI, Tapia JC. CK2 inhibition with silmitasertib promotes methuosis-like cell death associated to catastrophic massive vacuolization of colorectal cancer cells. Cell Death Dis. 2019 Jan 25;10(2):73. doi: 10.1038/s41419-019-1306-x. PMID: 30683840; PMCID: PMC6347595. 3. Richter A, Sender S, Lenz A, Schwarz R, Hinz B, Knuebel G, Sekora A, Murua Escobar H, Junghanss C, Roolf C. Influence of Casein kinase II inhibitor CX-4945 on BCL6-mediated apoptotic signaling in B-ALL in vitro and in vivo. BMC Cancer. 2020 Mar 4;20(1):184. doi: 10.1186/s12885-020-6650-9. PMID: 32131762; PMCID: PMC7057698 4. Rossi M, Ruiz de Azua I, Barella LF, Sakamoto W, Zhu L, Cui Y, Lu H, Rebholz H, Matschinsky FM, Doliba NM, Butcher AJ, Tobin AB, Wess J. CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo. Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):E6818-24. doi: 10.1073/pnas.1519430112. Epub 2015 Nov 23. PMID: 26598688; PMCID: PMC4679045.

In vitro protocol:

In vivo protocol:

1. Richter A, Sender S, Lenz A, Schwarz R, Hinz B, Knuebel G, Sekora A, Murua Escobar H, Junghanss C, Roolf C. Influence of Casein kinase II inhibitor CX-4945 on BCL6-mediated apoptotic signaling in B-ALL in vitro and in vivo. BMC Cancer. 2020 Mar 4;20(1):184. doi: 10.1186/s12885-020-6650-9. PMID: 32131762; PMCID: PMC7057698. 2. Rossi M, Ruiz de Azua I, Barella LF, Sakamoto W, Zhu L, Cui Y, Lu H, Rebholz H, Matschinsky FM, Doliba NM, Butcher AJ, Tobin AB, Wess J. CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo. Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):E6818-24. doi: 10.1073/pnas.1519430112. Epub 2015 Nov 23. PMID: 26598688; PMCID: PMC4679045.

1: Son YH, Moon SH, Kim J. The protein kinase 2 inhibitor CX-4945 regulates osteoclast and osteoblast differentiation In vitro. Mol Cells. 2013 Nov;36(5):417-23. doi: 10.1007/s10059-013-0184-9. Epub 2013 Oct 22. PubMed PMID: 24293011. 2: Quotti Tubi L, Gurrieri C, Brancalion A, Bonaldi L, Bertorelle R, Manni S, Pavan L, Lessi F, Zambello R, Trentin L, Adami F, Ruzzene M, Pinna LA, Semenzato G, Piazza F. Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity. J Hematol Oncol. 2013 Oct 12;6(1):78. doi: 10.1186/1756-8722-6-78. PubMed PMID: 24283803; PubMed Central PMCID: PMC3852751. 3: Buontempo F, Orsini E, Martins LR, Antunes I, Lonetti A, Chiarini F, Tabellini G, Evangelisti C, Evangelisti C, Melchionda F, Pession A, Bertaina A, Locatelli F, McCubrey JA, Cappellini A, Barata JT, Martelli AM. Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling. Leukemia. 2013 Nov 20. doi: 10.1038/leu.2013.349. [Epub ahead of print] PubMed PMID: 24253024. 4: Kim J, Hwan Kim S. CK2 inhibitor CX-4945 blocks TGF-β1-induced epithelial-to-mesenchymal transition in A549 human lung adenocarcinoma cells. PLoS One. 2013 Sep 4;8(9):e74342. doi: 10.1371/journal.pone.0074342. PubMed PMID: 24023938; PubMed Central PMCID: PMC3762800. 5: Martins LR, LÃºcio P, MelÃ£o A, Antunes I, Cardoso BA, Stansfield R, Bertilaccio MT, Ghia P, Drygin D, Silva MG, Barata JT. Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia. Leukemia. 2013 Aug 8. doi: 10.1038/leu.2013.232. [Epub ahead of print] PubMed PMID: 23925046. 6: Prins RC, Burke RT, Tyner JW, Druker BJ, Loriaux MM, Spurgeon SE. CX-4945, a selective inhibitor of casein kinase-2 (CK2), exhibits anti-tumor activity in hematologic malignancies including enhanced activity in chronic lymphocytic leukemia when combined with fludarabine and inhibitors of the B-cell receptor pathway. Leukemia. 2013 Oct;27(10):2094-6. doi: 10.1038/leu.2013.228. Epub 2013 Jul 31. PubMed PMID: 23900138. 7: Son YH, Song JS, Kim SH, Kim J. Pharmacokinetic characterization of CK2 inhibitor CX-4945. Arch Pharm Res. 2013 Jul;36(7):840-5. doi: 10.1007/s12272-013-0103-9. Epub 2013 Mar 31. PubMed PMID: 23543629. 8: Zanin S, Borgo C, Girardi C, O'Brien SE, Miyata Y, Pinna LA, Donella-Deana A, Ruzzene M. Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells. PLoS One. 2012;7(11):e49193. doi: 10.1371/journal.pone.0049193. Epub 2012 Nov 8. PubMed PMID: 23145120; PubMed Central PMCID: PMC3493520. 9: Kim J, Kim SH. Druggability of the CK2 inhibitor CX-4945 as an anticancer drug and beyond. Arch Pharm Res. 2012 Aug;35(8):1293-6. doi: 10.1007/s12272-012-0800-9. PubMed PMID: 22941473. 10: Siddiqui-Jain A, Bliesath J, Macalino D, Omori M, Huser N, Streiner N, Ho CB, Anderes K, Proffitt C, O'Brien SE, Lim JK, Von Hoff DD, Ryckman DM, Rice WG, Drygin D. CK2 inhibitor CX-4945 suppresses DNA repair response triggered by DNA-targeted anticancer drugs and augments efficacy: mechanistic rationale for drug combination therapy. Mol Cancer Ther. 2012 Apr;11(4):994-1005. doi: 10.1158/1535-7163.MCT-11-0613. Epub 2012 Jan 20. PubMed PMID: 22267551.