1. Cell Cycle/DNA Damage
  2. DNA/RNA Synthesis

CX-5461 

Cat. No.: HY-13323 Purity: 98.47%
Data Sheet SDS Handling Instructions

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

For research use only. We do not sell to patients.
CX-5461 Chemical Structure

CX-5461 Chemical Structure

CAS No. : 1138549-36-6

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  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

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

IC50 & Target

IC50: 142 nM (rRNA synthesis)

In Vitro

CX-5461 is found to selectively inhibit rRNA synthesis (Pol I IC50=142 nM; Pol II IC50 > 25 μM; selectivity appr 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 appr 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]. Eμ-Myc lymphoma cells from tumor-bearing mice are exquisitely sensitive to CX-5461 with an IC50 of 27.3 nM±8.1 nM for Pol I transcription after 1 hr and IC50 of 5.4 nM ±2.1 nM for cell death after 16 hr. CX-5461 activates p53 via the nucleolar stress response in Eμ-MycLymphoma Cells[2].

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]. CX-5461 (50 mg/kg) inhibits the Eμ-Myc tumor cells with 84% repression in Pol I transcription at 1 hr posttreatment. CX-5461 induces a rapid reduction in tumor burden in the lymph nodes and a concomitant reduction of spleen size to within the normal range[2].

Clinical Trial
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References
Preparing Stock Solutions
Concentration Volume Mass 1 mg 5 mg 10 mg
1 mM 1.9470 mL 9.7350 mL 19.4700 mL
5 mM 0.3894 mL 1.9470 mL 3.8940 mL
10 mM 0.1947 mL 0.9735 mL 1.9470 mL
Please refer to the solubility information to select the appropriate solvent.
Kinase Assay
[1]

Two short-lived RNA transcripts (half-lives appr 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 serves as the Pol I transcript and the mRNA for the protooncogene c-myc serves 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. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

Cells are plated on 96-well plates and treated the next day with dose response of drugs for 96 hours. Cell viability is determined using Alamar Blue and CyQUANT assays. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

Animal experiments are performed with 5- to 6-week-old female athymic (NCr nu/nu fisol) mice of Balb/c. Mice are inoculated with 5×106 in 100 μL of cell suspension subcutaneously in the right flank. Tumor measurements are performed by caliper analysis, and tumor volume is calculated using the formula (l×w2)/2, where w=width and l=length in mm of the tumor. established tumors (appr 110-120 mm3) are randomized into vehicle (50 mM NaH2PO4, pH 4.5), gemcitabine, or CX-5461 treatment groups. Tumor growth inhibition (TGI) is determined on the last day of study according to the formula: TGI (%)=[100 − (VfD− ViD)/ (VfV − ViV) × 100], where ViV is the initial mean tumor volume in vehicle-treated group, VfV is the final mean tumor volume in vehicle-treated group, ViD is the initial mean tumor volume in drug-treated group, and VfD is the final mean tumor volume in drug-treated group. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

513.61

Formula

C₂₇H₂₇N₇O₂S

CAS No.

1138549-36-6

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: < 5.3 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 98.47%

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CX-5461
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HY-13323
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