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
5.0mg USD 120.0 Ready to ship
10.0mg USD 190.0 Ready to ship
25.0mg USD 350.0 Ready to ship
50.0mg USD 550.0 Ready to ship
100.0mg USD 950.0 Ready to ship
200.0mg USD 1650.0 Ready to ship
500.0mg USD 2750.0 Ready to ship
1.0g USD 3650.0 Ready to ship
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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: Hilton J, Gelmon K, Bedard PL, Tu D, Xu H, Tinker AV, Goodwin R, Laurie SA, Jonker D, Hansen AR, Veitch ZW, Renouf DJ, Hagerman L, Lui H, Chen B, Kellar D, Li I, Lee SE, Kono T, Cheng BYC, Yap D, Lai D, Beatty S, Soong J, Pritchard KI, Soria-Bretones I, Chen E, Feilotter H, Rushton M, Seymour L, Aparicio S, Cescon DW. Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies. Nat Commun. 2022 Jun 24;13(1):3607. doi: 10.1038/s41467-022-31199-2. PMID: 35750695; PMCID: PMC9232501.

2: Głowacka A, Kilańczyk E, Maksymowicz M, Zawadzka M, Leśniak W, Filipek A. RNA-Seq Transcriptome Analysis of Differentiated Human Oligodendrocytic MO3.13 Cells Shows Upregulation of Genes Involved in Myogenesis. Int J Mol Sci. 2022 May 25;23(11):5969. doi: 10.3390/ijms23115969. PMID: 35682649; PMCID: PMC9181232.

3: Alam MS, Sultana A, Reza MS, Amanullah M, Kabir SR, Mollah MNH. Integrated bioinformatics and statistical approaches to explore molecular biomarkers for breast cancer diagnosis, prognosis and therapies. PLoS One. 2022 May 26;17(5):e0268967. doi: 10.1371/journal.pone.0268967. PMID: 35617355; PMCID: PMC9135200.

4: Okamoto T, Natsume Y, Doi M, Nosato H, Iwaki T, Yamanaka H, Yamamoto M, Kawachi H, Noda T, Nagayama S, Sakanashi H, Yao R. Integration of human inspection and artificial intelligence-based morphological typing of patient- derived organoids reveals interpatient heterogeneity of colorectal cancer. Cancer Sci. 2022 May 18. doi: 10.1111/cas.15396. Epub ahead of print. PMID: 35585758.

5: Jamroskovic J, Deiana M, Sabouri N. Probing the folding pathways of four- stranded intercalated cytosine-rich motifs at single base-pair resolution. Biochimie. 2022 Aug;199:81-91. doi: 10.1016/j.biochi.2022.04.007. Epub 2022 Apr 20. PMID: 35452743.

6: Tsoi H, You CP, Leung MH, Man EPS, Khoo US. Targeting Ribosome Biogenesis to Combat Tamoxifen Resistance in ER+ve Breast Cancer. Cancers (Basel). 2022 Feb 28;14(5):1251. doi: 10.3390/cancers14051251. PMID: 35267559; PMCID: PMC8909264.

7: Lehman SL, Schwartz KR, Maheshwari S, Camphausen K, Tofilon PJ. CX-5461 induces radiosensitization through modification of the DNA damage response and not inhibition of RNA polymerase I. Sci Rep. 2022 Mar 8;12(1):4059. doi: 10.1038/s41598-022-07928-4. PMID: 35260696; PMCID: PMC8904802.

8: Leung AWY, Chen KTJ, Ryan GM, Anantha M, Wretham N, Nosrati Z, Heroux D, Wang L, Chow N, Dai Z, Bally MB. DMPC/Chol liposomal copper CX5461 is therapeutically superior to a DSPC/Chol formulation. J Control Release. 2022 May;345:75-90. doi: 10.1016/j.jconrel.2022.03.004. Epub 2022 Mar 5. PMID: 35259461.

9: Kang CW, Hannan KM, Blackburn AC, Loh AHP, Hong KC, Yuan GJ, Hein N, Drygin D, Hannan RD, Coupland LA. The therapeutic potential of RNA Polymerase I transcription inhibitor, CX-5461, in uterine leiomyosarcoma. Invest New Drugs. 2022 Jun;40(3):529-536. doi: 10.1007/s10637-022-01222-w. Epub 2022 Feb 24. PMID: 35201535; PMCID: PMC9098598.

10: Pan G, Zhang J, Han Y, Chen Y, Guo X, Cui X, Cheng M, Gao H, Wang J, Jiang F. CX-5461 is a potent immunosuppressant which inhibits T cell-mediated alloimmunity via p53-DUSP5. Pharmacol Res. 2022 Mar;177:106120. doi: 10.1016/j.phrs.2022.106120. Epub 2022 Feb 4. PMID: 35131482.

11: Dannheisig DP, Schimansky A, Donow C, Pfister AS. Nucleolar Stress Functions Upstream to Stimulate Expression of Autophagy Regulators. Cancers (Basel). 2021 Dec 10;13(24):6220. doi: 10.3390/cancers13246220. PMID: 34944838; PMCID: PMC8699128.

12: Liano D, Chowdhury S, Di Antonio M. Cockayne Syndrome B Protein Selectively Resolves and Interact with Intermolecular DNA G-Quadruplex Structures. J Am Chem Soc. 2021 Dec 15;143(49):20988-21002. doi: 10.1021/jacs.1c10745. Epub 2021 Dec 2. PMID: 34855372.

13: Pan M, Wright WC, Chapple RH, Zubair A, Sandhu M, Batchelder JE, Huddle BC, Low J, Blankenship KB, Wang Y, Gordon B, Archer P, Brady SW, Natarajan S, Posgai MJ, Schuetz J, Miller D, Kalathur R, Chen S, Connelly JP, Babu MM, Dyer MA, Pruett-Miller SM, Freeman BB 3rd, Chen T, Godley LA, Blanchard SC, Stewart E, Easton J, Geeleher P. The chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma. Nat Commun. 2021 Nov 9;12(1):6468. doi: 10.1038/s41467-021-26640-x. PMID: 34753908; PMCID: PMC8578635.

14: Cornelison R, Biswas K, Llaneza DC, Harris AR, Sosale NG, Lazzara MJ, Landen CN. CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer. Cancers (Basel). 2021 Oct 9;13(20):5056. doi: 10.3390/cancers13205056. PMID: 34680204; PMCID: PMC8533980.

15: Wang S, Wong CC, Zhang Y, Huang J, Li C, Zhai J, Wang G, Wei H, Zhang X, He HH, Yu J. ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice. Oncogene. 2021 Dec;40(48):6590-6600. doi: 10.1038/s41388-021-01938-8. Epub 2021 Oct 6. PMID: 34615997; PMCID: PMC8639438.

16: Teng FY, Jiang ZZ, Guo M, Tan XZ, Chen F, Xi XG, Xu Y. G-quadruplex DNA: a novel target for drug design. Cell Mol Life Sci. 2021 Oct;78(19-20):6557-6583. doi: 10.1007/s00018-021-03921-8. Epub 2021 Aug 30. PMID: 34459951.

17: Xuan J, Gitareja K, Brajanovski N, Sanij E. Harnessing the Nucleolar DNA Damage Response in Cancer Therapy. Genes (Basel). 2021 Jul 28;12(8):1156. doi: 10.3390/genes12081156. PMID: 34440328; PMCID: PMC8393943.

18: Lawrence MG, Porter LH, Choo N, Pook D, Grummet JP, Pezaro CJ, Sandhu S, Ramm S, Luu J, Bakshi A, Goode DL, Sanij E, Pearson RB, Hannan RD, Simpson KJ, Taylor RA, Risbridger GP, Furic L. CX-5461 Sensitizes DNA Damage Repair- proficient Castrate-resistant Prostate Cancer to PARP Inhibition. Mol Cancer Ther. 2021 Nov;20(11):2140-2150. doi: 10.1158/1535-7163.MCT-20-0932. Epub 2021 Aug 19. PMID: 34413130.

19: Liao H, Gaur A, Mauvais C, Denicourt C. p53 induces a survival transcriptional response after nucleolar stress. Mol Biol Cell. 2021 Oct 1;32(20):ar3. doi: 10.1091/mbc.E21-05-0251. Epub 2021 Jul 28. PMID: 34319761; PMCID: PMC8684752.

20: Pang S, Chen Y, Dai C, Liu T, Zhang W, Wang J, Cui X, Guo X, Jiang F. Anti- fibrotic effects of p53 activation induced by RNA polymerase I inhibitor in primary cardiac fibroblasts. Eur J Pharmacol. 2021 Sep 15;907:174303. doi: 10.1016/j.ejphar.2021.174303. Epub 2021 Jul 1. PMID: 34217709.

CX-5461

5.0mg / USD 120.0


Additional Information