Pidnarulex (CX-5461)

Catalog No.S2684 Batch:S268405

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Technical Data

Formula

C27H27N7O2S
Molecular Weight 513.61 CAS No. 1138549-36-6
Solubility (25°C)* In vitro DMSO Insoluble
Water Insoluble
Ethanol Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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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 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 (from reference)

Kinase Assay:[1]
  • 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 Assay:[1]
  • 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
Animal Study:[1]
  • 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.

Customer Product Validation

Data from [Data independently produced by PLoS One, 2014, 9(8), e104364]

Data from [Data independently produced by , , Cell, 2018, 174(2):338-349]

Data from [Data independently produced by , , Oncogene, 2015, 10.1038/onc.2015.147]

Data from [Data independently produced by , , J Control Release, 2018, 286:1-9]

Selleck's Pidnarulex (CX-5461) has been cited by 69 publications

VAV2 orchestrates the interplay between regenerative proliferation and ribogenesis in both keratinocytes and oral squamous cell carcinoma [ Sci Rep, 2024, 14(1):4060] PubMed: 38374399
Integrated drug response prediction models pinpoint repurposed drugs with effectiveness against rhabdomyosarcoma [ PLoS One, 2024, 19(1):e0295629] PubMed: 38277404
CX‑5461 potentiates imatinib‑induced apoptosis in K562 cells by stimulating KIF1B expression [ Exp Ther Med, 2024, 27(3):107.] PubMed: 38356673
CX‑5461 potentiates imatinib‑induced apoptosis in K562 cells by stimulating KIF1B expression [ Exp Ther Med, 2024, 27(3):107] PubMed: 38356673
USP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress [ Nat Commun, 2023, 14(1):6473] PubMed: 37833415
USP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress [ Nat Commun, 2023, 14(1):6473] PubMed: 37833415
Repression of rRNA gene transcription by endothelial SPEN deficiency normalizes tumor vasculature via nucleolar stress [ J Clin Invest, 2023, 133(20)e159860] PubMed: 37607001
Viscoelasticity and advective flow of RNA underlies nucleolar form and function [ Mol Cell, 2023, 83(17):3095-3107.e9] PubMed: 37683610
KMT2D Deficiency Promotes Myeloid Leukemias which Is Vulnerable to Ribosome Biogenesis Inhibition [ Adv Sci (Weinh), 2023, 10(19):e2206098] PubMed: 37142882
Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET [ Cell Death Differ, 2023, 10.1038/s41418-023-01167-4] PubMed: 37142656

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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