Pidnarulex (CX-5461)

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

Pidnarulex (CX-5461) Chemical Structure

CAS: 1138549-36-6

Selleck's Pidnarulex (CX-5461) has been cited by 67 publications

Purity & Quality Control

Batch: Purity: 99.07%
99.07

Pidnarulex (CX-5461) Related Products

Choose Selective DNA/RNA Synthesis Inhibitors

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation 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 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.
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
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 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, 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]
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
NCT02719977 Completed
Cancer
Canadian Cancer Trials Group|Senhwa Biosciences Inc.|Stand Up To Cancer
June 13 2016 Phase 1

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)

In vitro
Batch:

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

Water : Insoluble

Ethanol : Insoluble


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In vivo
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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.

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