Pidnarulex free base | CAS#1138549-36-6 | RNA polymerase inhibitor

MedKoo Cat#: 200848 | Name: CX-5461

Description:

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

Pidnarulex (CX-5461) is a small-molecule inhibitor that selectively targets RNA polymerase I–mediated rRNA synthesis, exhibiting potent anticancer activity, particularly in tumors with defective homologous recombination (HR) repair mechanisms such as BRCA1/2 mutations. It stabilizes G-quadruplex DNA structures and induces replication stress and DNA damage, leading to synthetic lethality in HR-deficient cancer cells. Preclinical studies have shown nanomolar potency against a range of HR-deficient tumor cell lines, with GI₅₀ values typically in the range of 50–150 nM. In vivo, CX-5461 has demonstrated significant tumor regression in BRCA-deficient xenograft models

Chemical Structure

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: 513.1947

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
5mg	USD 120.00	Ready to ship
10mg	USD 190.00	Ready to ship
25mg	USD 350.00	Ready to ship
50mg	USD 550.00	Ready to ship
100mg	USD 950.00	Ready to ship
200mg	USD 1,650.00	Ready to ship
500mg	USD 2,750.00	Ready to ship
1g	USD 3,650.00	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; Pidnarulex free base

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

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A8T12K07

QC Data

View QC data: current batch, Lot#A8T12K07

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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/

	Solvent	mg/mL	mM
Solubility
	DMSO	1.0	1.97
	DMF	2.0	3.98
	DMF:PBS (pH 7.2) (1:1)	0.5	0.97
	Ethanol	0.1	0.10

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 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.

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:

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.

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.