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Pidnarulex (CX-5461)

Name: Pidnarulex (CX-5461)
Brand: Selleck Chemicals
SKU: S2684
Rating: 5 (71 reviews)

Catalog No.S2684 Purity:99.07%

Pidnarulex (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.

Pidnarulex (CX-5461) Chemical Structure

CAS No. 1138549-36-6

Purity & Quality Control

Batch: Purity: 99.07%

99.07

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Signaling Pathway

DNA/RNA Synthesis Signaling Pathway

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	Activity Description	PMID
MNNG	Cell viability assay		72 h	IC50=0.5-1.5 µM	27729807
U2-OS	Cell viability assay		72 h	IC50=0.5-1.5 µM	27729807
RS4;11	Proliferation assay	250 nM	24 h	time dependent decrease in proliferation relative to their DMSO treated controls	26472108
SEM	Proliferation assay	250 nM	24 h	time dependent decrease in proliferation relative to their DMSO treated controls	26472108
KOPN-8	Proliferation assay	250 nM	24 h	time dependent decrease in proliferation relative to their DMSO treated controls	26472108
NALM-6	Proliferation assay	250 nM	24 h	time dependent decrease in proliferation relative to their DMSO treated controls	26472108
NB-EBc1	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells	29435139
Click to View More Cell Line Experimental Data

Biological Activity

Description

Targets

Pol I-driven transcription of rRNA ^[1]
(HCT-116, A375, MIA PaCa-2 cells)

142 nM

In vitro
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]
Kinase Assay	Pol I and Pol II Transcription Assay
Kinase 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, cellsare 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	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
Experimental Result Images	Methods	Biomarkers	Images	PMID
	Western blot	Cyclin D1 / p53 / p16 53BP1 / γ-H2AX / p-ATM Bcl-2 / Bax / Caspase3 cleaved PARP / cleaved Caspase-9 / cleaved caspase-3 p-AMPK / AMPK / p-mTOR / mTOR EG5 / Histone H3 / p-Histone H3 (S10)		29631594
	Immunofluorescence	Vimentin / Phalloidin / Snail1 Rictor / Calnexin Fibrillarin LC3 γH2AX / 53BP1 / RPA / RAD51 chromosome / telomere F-actin / Aurora B		31068593
	Growth inhibition assay	Cell viability		26061708

In Vivo
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. Likewise, CX- 5461 demonstrates significant A375 TGI with TGI equal to 79% on day 32. ^[1]
Animal Research	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
	Dosages	50 mg/kg
	Administration	CX-5461 is administered orally once daily or every 3 days.

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT02719977	Completed	Cancer	Canadian Cancer Trials Group\|Senhwa Biosciences Inc.\|Stand Up To Cancer	June 13 2016	Phase 1

References

[1] Drygin D, et al, Cancer Res, 2011, 71(4), 1418-1430.

Chemical Information & Solubility

Molecular Weight	513.61	Formula	C₂₇H₂₇N₇O₂S
CAS No.	1138549-36-6	SDF	Download Pidnarulex (CX-5461) SDF
Smiles	CC1=CN=C(C=N1)CNC(=O)C2=C3N(C4=CC=CC=C4S3)C5=C(C2=O)C=CC(=N5)N6CCCN(CC6)C
Storage (From the date of receipt)	3 years-20°Cpowder	Storage of Stock Solutions Aliquot the stock solutions to avoid repeated freeze-thaw cycles	1 year-80°Cin solvent
Storage (From the date of receipt)	3 years-20°Cpowder		1 month-20°Cin solvent

In vitro
Batch:

DMSO : Insoluble ( Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molecular Weight Calculator

In vivo Batch: Add solvents to the product individually and in order.					In vivo Formulation Calculator
	Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O	0.15mg/ml (0.29mM)	Taking the 1 mL working solution as an example, add 50 μL of 3 mg/ml clarified DMSO stock solution to 400 μL PEG300, mix evenly to clarify it; add 50 μL Tween80 to the above system, mix evenly to clarify it; then continue to add 500 μL ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.	In vivo Formulation Calculator
Clear solution	5% DMSO 1 95% corn oil	0.15mg/ml (0.29mM)	Taking the 1 mL working solution as an example, add 50 μL of 3 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results.
Clear solution	5%DMF 1 40%PEG300 2 5%Tween80 3 50%ddH2O	2.0mg/ml (3.89mM)	Taking the 1 mL working solution as an example, add 50 μL 40 mg/ml clarified DMF stock solution to 400 μL PEG300, mix evenly to clarify it; add 50 μL Tween80 to the above system, mix evenly to clarify it; then continue to add 500 μL ddH2O to adjust the volume to 1 mL. . The mixed solution should be used immediately for optimal results.
Clear solution	5%DMF 1 95%Corn oil	2.0mg/ml (3.89mM)	Taking the 1 mL working solution as an example, add 50 μL of 40 mg/ml clarified DMF stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results.
Clear solution	5%DMF 1 95%Corn oil	2.0mg/ml (3.89mM)	Taking the 1 mL working solution as an example, add 50 μL of 40 mg/ml clarified DMF stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results.

Preparing Stock Solutions

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
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Dilution Calculator Molecular Weight Calculator

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

Dosage: mg/kg Average weight of animals: g Dosing volume per animal:μL Number of animals:

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

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

Tel: +1-832-582-8158 Ext:3
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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.

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