CX-5461
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.
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.
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.
| Chemical | |
|---|---|
| CAS Num | 1138549-36-6 |
| Chemical Formula | C27H27N7O2S |
| Molecular Weight | 513.61 |
| 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 |
| Exact Mass | 513.19469 |
| Elemental Analysis | C, 63.14; H, 5.30; N, 19.09; O, 6.23; S, 6.24 |
| Synonym | CX5461; CX 5461; CX-5461. |
| Solubility | Soluble in DMSO, not in water |
| 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 |
| Biological | |
| Targets and Effects | RNA polymerase inhibitor |
| Pathways | Apoptosis |
| Physical | |
| 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). |
| Shelf Life | >2 years if stored properly |
Mailing Address
Anba Pharma Company
3-H Gill Street, Suite 300
Woburn, MA 01801
United State
Our Contact Info.
Tel: 1+610-883-0668
Email: sales@AnbaPharma.com