CX-5461
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MedKoo CAT#: 200848

CAS#: 1138549-36-6 (free base)

Description: CX-5461 is a first-in-class non-genotoxic small molecule targeted inhibitor of RNA polymerase I (Pol I) that activates the p53 pathway without causing DNA damage. CX-5461 selectively inhibits rRNA synthesis by Pol I in the nucleolus, but does not inhibit mRNA synthesis by RNA Polymerase II (Pol II) and does not inhibit DNA replication or protein synthesis. Inhibition of Pol I results in nucleolar stress and release of ribosomal proteins (RP) from the nucleolus. The RP bind to Mdm2 and liberate p53 to orchestrate apoptosis in cancer cells. CX-5461 demonstrates a favorable preclinical profile, potently and selectively kills cancer cells, demonstrates robust in vivo efficacy in multiple models, and has demonstrated oral bioavailability in multiple species.


Chemical Structure

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CX-5461
CAS# 1138549-36-6 (free base)

Theoretical Analysis

MedKoo Cat#: 200848
Name: CX-5461
CAS#: 1138549-36-6 (free base)
Chemical Formula: C27H27N7O2S
Exact Mass: 513.19469
Molecular Weight: 513.61
Elemental Analysis: C, 63.14; H, 5.30; N, 19.09; O, 6.23; S, 6.24

Price and Availability

Size Price Availability Quantity
10.0mg USD 190.0 Same day
25.0mg USD 350.0 Same day
50.0mg USD 550.0 Same day
100.0mg USD 950.0 Same day
200.0mg USD 1650.0 Same day
500.0mg USD 2750.0 Same day
1.0g USD 3650.0 Same day
2.0g USD 6450.0 2 Weeks
5.0g USD 12650.0 2 Weeks
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Related CAS #: 2101314-20-7 (HCl)   1138549-36-6 (free base)  

Synonym: CX5461; CX 5461; CX-5461; Pidnarulex

IUPAC/Chemical Name: 2-(4-methyl-1,4-diazepan-1-yl)-N-((5-methylpyrazin-2-yl)methyl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide

InChi Key: XGPBJCHFROADCK-UHFFFAOYSA-N

InChi Code: InChI=1S/C27H27N7O2S/c1-17-14-29-18(15-28-17)16-30-26(36)23-24(35)19-8-9-22(33-11-5-10-32(2)12-13-33)31-25(19)34-20-6-3-4-7-21(20)37-27(23)34/h3-4,6-9,14-15H,5,10-13,16H2,1-2H3,(H,30,36)

SMILES Code: O=C(C1=C(SC2=CC=CC=C23)N3C4=C(C=CC(N5CCN(C)CCC5)=N4)C1=O)NCC6=NC=C(C)N=C6

Appearance: white 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, not in water

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

Biological target: CX-5461 inhibits RNA polymerase I-driven transcription of rRNA with IC50s of 142, 113, and 54 nM in HCT-116, A375, and MIA PaCa-2 cells, respectively.
In vitro activity: Pancreatic cancer has one of the highest rates of metastasis among solid cancers, and a better understanding of the anti-migratory effects of new drugs is essential in order to provide more effective tools for therapeutic purposes. The effect of CX-5461 on cell migration was investigated using a wound healing assay. CX-5461 treatment inhibited cell migration significantly at 16, 20, and 22 h after treatment, resulting in 40% cell migration in treated cells compared to 65% in untreated cells after 16 h (Figure 2a,b). Notably, at the more advanced time points of 20 and 22 h, the cell migration of CX-5461 treated cells remained 40%, compared to increased migration of the untreated cells. Reference: Molecules. 2019 Dec 4;24(24):4445. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943431/
In vivo activity: The potential of CX-5461 and PARPi (PARP inhibitors) interaction was investigated in vivo in a BRCA2-mutated, HR-deficient post one line of platinum treatment (high grade serious ovarian cancer) HGSOC-PDX (#19B) mouse model. The administration of CX-5461 as a single agent resulted in stable disease and a statistically significant survival benefit (median time to harvest (at ethical endpoint) (TTH) for CX-5461 treatment 53 days vs vehicle 22 days, p-value 0.00285 compared with vehicle) (Fig. 9a). Reference: Nat Commun. 2020 May 26;11(1):2641. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251123/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 1.01 1.97
DMF 2.0 3.98
DMF:PBS (pH 7.2) (1:1) 0.5 0.97
Ethanol 0.05 0.1

Preparing Stock Solutions

The following data is based on the product molecular weight 513.61 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.

Recalculate based on batch purity %
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. Xu H, Di Antonio M, McKinney S, Mathew V, Ho B, O'Neil NJ, Santos ND, Silvester J, Wei V, Garcia J, Kabeer F, Lai D, Soriano P, Banáth J, Chiu DS, Yap D, Le DD, Ye FB, Zhang A, Thu K, Soong J, Lin SC, Tsai AH, Osako T, Algara T, Saunders DN, Wong J, Xian J, Bally MB, Brenton JD, Brown GW, Shah SP, Cescon D, Mak TW, Caldas C, Stirling PC, Hieter P, Balasubramanian S, Aparicio S. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat Commun. 2017 Feb 17;8:14432. doi: 10.1038/ncomms14432. PMID: 28211448; PMCID: PMC5321743. 2. El Hassouni B, Mantini G, Immordino B, Peters GJ, Giovannetti E. CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage. Molecules. 2019 Dec 4;24(24):4445. doi: 10.3390/molecules24244445. PMID: 31817270; PMCID: PMC6943431. 3. Sanij E, Hannan KM, Xuan J, Yan S, Ahern JE, Trigos AS, Brajanovski N, Son J, Chan KT, Kondrashova O, Lieschke E, Wakefield MJ, Frank D, Ellis S, Cullinane C, Kang J, Poortinga G, Nag P, Deans AJ, Khanna KK, Mileshkin L, McArthur GA, Soong J, Berns EMJJ, Hannan RD, Scott CL, Sheppard KE, Pearson RB. CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer. Nat Commun. 2020 May 26;11(1):2641. doi: 10.1038/s41467-020-16393-4. PMID: 32457376; PMCID: PMC7251123.
In vitro protocol: 1. Xu H, Di Antonio M, McKinney S, Mathew V, Ho B, O'Neil NJ, Santos ND, Silvester J, Wei V, Garcia J, Kabeer F, Lai D, Soriano P, Banáth J, Chiu DS, Yap D, Le DD, Ye FB, Zhang A, Thu K, Soong J, Lin SC, Tsai AH, Osako T, Algara T, Saunders DN, Wong J, Xian J, Bally MB, Brenton JD, Brown GW, Shah SP, Cescon D, Mak TW, Caldas C, Stirling PC, Hieter P, Balasubramanian S, Aparicio S. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat Commun. 2017 Feb 17;8:14432. doi: 10.1038/ncomms14432. PMID: 28211448; PMCID: PMC5321743. 2. El Hassouni B, Mantini G, Immordino B, Peters GJ, Giovannetti E. CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage. Molecules. 2019 Dec 4;24(24):4445. doi: 10.3390/molecules24244445. PMID: 31817270; PMCID: PMC6943431.
In vivo protocol: 1. Sanij E, Hannan KM, Xuan J, Yan S, Ahern JE, Trigos AS, Brajanovski N, Son J, Chan KT, Kondrashova O, Lieschke E, Wakefield MJ, Frank D, Ellis S, Cullinane C, Kang J, Poortinga G, Nag P, Deans AJ, Khanna KK, Mileshkin L, McArthur GA, Soong J, Berns EMJJ, Hannan RD, Scott CL, Sheppard KE, Pearson RB. CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer. Nat Commun. 2020 May 26;11(1):2641. doi: 10.1038/s41467-020-16393-4. PMID: 32457376; PMCID: PMC7251123.

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1: Quin JE, Devlin JR, Cameron D, Hannan KM, Pearson RB, Hannan RD. Targeting the nucleolus for cancer intervention. Biochim Biophys Acta. 2014 Jun;1842(6):802-816. doi: 10.1016/j.bbadis.2013.12.009. Epub 2014 Jan 2. Review. PubMed PMID: 24389329.

2: Achiron A, Mashiach R, Zilkha-Falb R, Meijler MM, Gurevich M. Polymerase I pathway inhibitor ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol. 2013 Oct 15;263(1-2):91-7. doi: 10.1016/j.jneuroim.2013.08.002. Epub 2013 Aug 15. PubMed PMID: 23998422.

3: Bywater MJ, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C, Wall M, Cluse L, Drygin D, Anderes K, Huser N, Proffitt C, Bliesath J, Haddach M, Schwaebe MK, Ryckman DM, Rice WG, Schmitt C, Lowe SW, Johnstone RW, Pearson RB, McArthur GA, Hannan RD. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell. 2012 Jul 10;22(1):51-65. doi: 10.1016/j.ccr.2012.05.019. PubMed PMID: 22789538; PubMed Central PMCID: PMC3749732.

4: Drygin D, Lin A, Bliesath J, Ho CB, O'Brien SE, Proffitt C, Omori M, Haddach M, Schwaebe MK, Siddiqui-Jain A, Streiner N, Quin JE, Sanij E, Bywater MJ, Hannan RD, Ryckman D, Anderes K, Rice WG. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 2011 Feb 15;71(4):1418-30. doi: 10.1158/0008-5472.CAN-10-1728. Epub 2010 Dec 15. PubMed PMID: 21159662.

CX-5461

10.0mg / USD 190.0


Additional Information