CX-5461
CX-5461 is a potent and orally bioavailable small-molecule inhibitor of rRNA synthesis that specifically inhibits RNA polymerase (Pol) I-driven transcription with IC50 value of 142 nM. CX-5461 exhibits antiproliferative activity against human pancreatic tumor cells MIA Paca-2, human melanoma cells A375 and colorectal carcinoma cells HCT-116 with EC50 values of 74, 58, and 167 nmol/L, respectively. [1].
CX-5461 was revealed to inhibit Pol I transcription via promoting the stabilization of p53. In addition, CX-5461 has been demonstrated to induce autophagy and senescence but not apoptosis in MIA Paca-2 and A375 cell lines.
In vivo, CX-5461 has shown to suppress tumor volume in both MIA Paca-2 and A375 derived xenograft mice models [1].
References:
[1] Drygin D1, 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
- 1. Lorène Brunello, Jolanta Polanowska, et al."A nuclear protein quality control system for elimination of nucleolus-related inclusions." EMBO J (2024) 44: 801 - 823
- 2. Coral K Wille, Xiaoya Zhang, et al. "DOT1L is a barrier to histone acetylation during reprogramming to pluripotency." Sci Adv. 2023 Nov 15;9(46):eadf3980. PMID: 37976354
- 3. Guopin Pan, Jing Zhang, et al. "CX-5461 is a potent immunosuppressant which inhibits T cell-mediated alloimmunity via p53-DUSP5." Pharmacol Res. 2022 Mar;177:106120. PMID: 35131482
- 4. Zonneville J, Wong V, et al. "TAK1 signaling regulates p53 through a mechanism involving ribosomal stress." Sci Rep. 2020 Feb 13;10(1):2517. PMID: 32054925
- 5. Rossetti S, Wierzbicki AJ, et al. "Undermining ribosomal RNA transcription in both the nucleolus and mitochondrion: an offbeat approach to target MYC-driven cancer." Oncotarget. 2017 Dec 22;9(4):5016-5031. PMID: 29435159
- 6. Rossetti S, Wierzbicki AJ, et al. "Mammary epithelial morphogenesis and early breast cancer. Evidence of involvement of basal components of the RNA Polymerase I transcription machinery." Cell Cycle. 2016 Aug 2:0. PMID: 27485818
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 513.61 |
| Cas No. | 1138549-36-6 |
| Formula | C27H27N7O2S |
| Synonyms | CX 5461;CX5461 |
| Solubility | insoluble in H2O; insoluble in EtOH; insoluble in DMSO |
| Chemical Name | 2-(4-methyl-1,4-diazepan-1-yl)-N-[(5-methylpyrazin-2-yl)methyl]-5-oxo-[1,3]benzothiazolo[3,2-a][1,8]naphthyridine-6-carboxamide |
| SDF | Download SDF |
| Canonical SMILES | CC1=CN=C(C=N1)CNC(=O)C2=C3N(C4=CC=CC=C4S3)C5=C(C2=O)C=CC(=N5)N6CCCN(CC6)C |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell Experiments: [1] | |
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Cell lines |
hTERT-immortalized BJ-hTERT human fibroblasts, Human inflammatory breast cancer cell lines SUM 149PT and SUM 190PT, Human eosinophilic leukemia cell line EOL-1, human B cell precursor leukemia cell line SEM, and human acute monocytic leukemia cell line THP-1 |
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Preparation method |
Stored at room temperature as 10 mmol/L stock solutions in 50 mmol/L NaH2PO4?(pH 4.5) |
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Reacting condition |
2 μmol/L, 1 hour |
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Applications |
Treatment of HCT-116, A375, or MIA PaCa-2 with 2 μmol/L CX-5461 resulted in 40% to 60% reduction of the Pol I enzyme association with the rDNA promoter. CX-5461 significantly depleted the binding of Pol I transcription factors (TF) to the rDNA promoter in HCT-116 cells. In dose-response studies, the IC50?for inhibition of DNA synthesis in A375 and MIA PaCa-2 cell lines ranged from 16.8 to 27.9 μmol/L. Treatment of solid tumor cell lines with CX-5461 induced cellular senescence and autophagy through selective inhibition of rRNA synthesis. CX-5461 targets the SL1 transcription factor of the Pol I complex and induces autophagy and senescence among solid tumor cell lines and selectively kills cancer cells relative to normal cells. |
| Animal experiment: [1] | |
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Animal models |
Murine xenograft models of human cancers, pancreatic carcinoma (MIA PaCa-2) and melanoma (A375) |
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Dosage form |
Administered orally (50 mg/kg) either once daily or every 3 day |
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Application |
In murine xenograft models bearing human melanoma cancers (A375), CX-5461 demonstrated significant TGI with TGI equal to 79% on day 32. Human solid tumors grown in murine xenograft models revealed that CX-5461 can be orally administered with favorable pharmacokinetics and an antitumor efficacy. CX-5461 was well tolerated at all tested schedules as judged by the absence of significant changes in animal body weights or overt toxicity.? |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: 1. Drygin D, Lin A, Bliesath J, et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth[J]. Cancer research, 2011, 71(4): 1418-1430. |
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| Description | CX-5461 is an inhibitor of rRNA synthesis with IC50 of 142 nM for Pol I-driven transcription of rRNA, | |||||
| Targets | Pol I | HCT-116 | A375 | MIA PaCa-2 | ||
| IC50 | 142 nM | 167 nM (ED50) | 58 nM (ED50) | 74 nM (ED50) | ||
Quality Control & MSDS
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Chemical structure
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