CX-5461

Catalog No.S2684

CX-5461 Chemical Structure

Molecular Weight(MW): 513.61

CX-5461 is an inhibitor of rRNA synthesis, selectively inhibits Pol I-driven transcription of rRNA with IC50 of 142 nM in HCT-116, A375, and MIA PaCa-2 cells, has no effect on Pol II, and possesses 250- to 300-fold selectivity for inhibition of rRNA transcription versus DNA replication and protein translation.

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2 Customer Reviews

  • Representative western blot evaluation and densitormetric analysis of p53 expression in control and CX-5461 (CX)-treated HCT116, HepG2, MCF7 and LoVo cells. Cells were exposed to 1 μM CX-5461 for 12 h.

    Oncogene, 2015, 10.1038/onc.2015.147. CX-5461 purchased from Selleck.

    The specific Pol I inhibitor CX-5461 causes nucleolar disruption, blocks LTP maintenance and Fsk-induced synthesis of new rRNA. DAPI staining (blue; A, B,C) shows the area of the nucleus. Nomarski images (grey; G, H,I) show the area of the nuclei and nucleoli (arrowheads). Application of Pol I specific inhibitor CX-5461 (200 nM) causes nucleolar disruption as indicated by the distribution of fibrillarin (green); compare A, D to B, E and C, F.

    PLoS One 2014 9(8), e104364. CX-5461 purchased from Selleck.

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Notes:

2. For more details, such as half maximal inhibitory concentrations (IC50s) and working concentrations of each inhibitor, please click on the link of the inhibitor of interest.
3. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation.
4. Orange "√" refers to compounds which do inhibitory effects on the related isoform, but without specific value.

Biological Activity

Description CX-5461 is an inhibitor of rRNA synthesis, selectively inhibits Pol I-driven transcription of rRNA with IC50 of 142 nM in HCT-116, A375, and MIA PaCa-2 cells, has no effect on Pol II, and possesses 250- to 300-fold selectivity for inhibition of rRNA transcription versus DNA replication and protein translation.
Targets
A375 [1] MIA PaCa-2 [1] Pol I-driven transcription of rRNA [1]
(HCT-116, A375, MIA PaCa-2 cells)
HCT-116 [1]
58 nM(ED50) 74 nM(ED50) 142 nM 167 nM(ED50)
In vitro

CX-5461 is found to selectively inhibit rRNA synthesis (Pol I IC50=142 nM; Pol II IC50 > 25 μM; selectivity ~200-fold) in the HCT-116 cells. Selective inhibition of rRNA synthesis by CX-5461 is confirmed in two other human solid tumor cell lines; melanoma A375 (Pol I IC50 = 113 nM; Pol II IC50 > 25 μM) and pancreatic carcinoma MIA PaCa-2 (Pol I IC50=54 nM; Pol II IC50 ~25 mM). CX-5461 possesses 250- to 300-fold selectivity for inhibition of rRNA transcription versus DNA replication and protein translation. CX-5461 exhibits broad antiproliferative potency in a panel of cancer cell lines in human cancer cell lines, but has minimal effect on viability of nontransformed human cells. The median EC50 across all tested cell lines is 147 nM, yet all normal cell lines have EC50 values of approximately 5, 000 nM. Evaluation of the antiproliferative dose response for HCT-116, A375, and MIA PaCa-2 cell lines yield EC50 values of 167, 58, and 74 nM. CX-5461 induces autophagy and senescence in solid tumor cancer cells, rather than apoptosis, through a p53-independent process. [1]

In vivo CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. CX-5461 demonstrates significant MIA PaCa-2 TGI with TGI equal to 69% on day 31, comparable to that of gemcitabine (63% TGI). Gemcitabine is a positive control which is administered intraperitoneally once every 3 days at 120 mg/kg. Likewise, CX- 5461 demonstrates significant A375 TGI with TGI equal to 79% on day 32. [1]

Protocol

Kinase Assay
+ Expand

Pol I and Pol II Transcription Assay:

Two short-lived RNA transcripts (half-lives ~20-30 minutes), one produced by Pol I and another by Pol II, are quantitated by qRT-PCR as a measure of CX-5461-related effects on transcription. The 45S pre-rRNA served as the Pol I transcript and the mRNA for the protooncogene c-myc served as the comparator Pol II transcript. Both Pol I and Pol II transcription are known to be affected by general cellular stress. To minimize the potential effects of such stress, cells are exposed to test agents for only a short period of time (2 hours). This is sufficient time for these transcripts to be reduced by greater than 90% if CX-5461 affects their synthesis.
Cell Research
+ Expand
  • Cell lines: panel of cancer and normal cell lines
  • Concentrations: 0-2 μM
  • Incubation Time: 96 hours
  • Method: Cells are plated on 96-well plates and treated the next day with dose response of CX-5461 for 96 hours. Cell viability is determined using Alamar Blue and CyQUANT assays
    (Only for Reference)
Animal Research
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  • Animal Models: 5 × 106 MIA Paca-2 and A375 cancer cells are subcutaneously inoculated in the right flank of 5- to 6- week-old female athymic mice
  • Formulation: CX-5461 is dissolved in 50 mM NaH2PO4 (pH 4.5).
  • Dosages: 50 mg/kg
  • Administration: CX-5461 is administered orally once daily or every 3 days.
    (Only for Reference)

Solubility (25°C)

In vitro DMF 3 mg/mL (5.84 mM) warming
DMSO 0.02 mg/mL (0.03 mM)
Water <1 mg/mL
In vivo

* 1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 513.61
Formula

C27H27N7O2S

CAS No. 1138549-36-6
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02719977 Recruiting Cancer Canadian Cancer Trials Group|Senhwa Biosciences, Inc.|Stand Up To Cancer May 2016 Phase 1|Phase 2

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Frequently Asked Questions

  • Question 1:

    I want to make it for further in vivo treatment. I

  • Answer:

    The solubility of this compound is poor in common vehicles. It can be dissolved in DMF at 3 mg/ml with warming.

DNA/RNA Synthesis Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID