Pidnarulex (CX-5461)

Catalog No.S2684

For research use only.

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

Selleck's Pidnarulex (CX-5461) has been cited by 51 publications

Purity & Quality Control

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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]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MNNG MoK4R4VtdCC4aXHibYxqfHliYYPzZZk> MX63NkBp NUnBSGd{UUN3ME2wMlUuOS53INM1US=> NH3PNW09[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{N{eyPVgxPyd-Mke3Nlk5ODd:L3G+
U2-OS M2HsXGNmdGxidnnhZoltcXS7IHHzd4F6 M4LmOFczKGh? Ml\5TWM2OD1yLkWtNU42KML3TR?= MkPsQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjd5Mkm4NFcoRjJ5N{K5PFA4RC:jPh?=
RS4;11 NX;DfYlkWHKxbHnm[ZJifGmxbjDhd5NigQ>? NFXTc5EzPTBibl2= MoXyNlQhcA>? MnfGeIlu\SCmZYDlcoRmdnRiZHXjdoVie2ViaX6gdJJwdGmoZYLheIlwdiC{ZXzheIl3\SC2bzD0bIVqeiCGTWPPJJRz\WG2ZXSgZ49vfHKxbIO= MXm8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPjR5MkGwPEc,OjZ2N{KxNFg9N2F-
SEM NX:0R|NXWHKxbHnm[ZJifGmxbjDhd5NigQ>? MoTlNlUxKG6P MkHjNlQhcA>? MWf0bY1mKGSncHXu[IVvfCCmZXPy[YF{\SCrbjDwdo9tcW[ncnH0bY9vKHKnbHH0bZZmKHSxIITo[YlzKESPU1:geJJm[XSnZDDjc451em:ucx?= NVL0eHlORGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMk[0O|IyODhpPkK2OFczOTB6PD;hQi=>
KOPN-8 MnnoVJJwdGmoZYLheIlwdiCjc4PhfS=> MY[yOVAhdk1? MWqyOEBp NEjCO|l1cW2nIHTldIVv\GWwdDDk[YNz\WG|ZTDpckBxem:uaX\ldoF1cW:wIILlcIF1cX[nIITvJJRp\Wm{IFTNV28hfHKnYYTl[EBkd262cn;sdy=> M2TBWVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ4NEeyNVA5Lz5{NkS3NlExQDxxYU6=
NALM-6 MX\Qdo9tcW[ncnH0bY9vKGG|c3H5 MoTFNlUxKG6P MmDFNlQhcA>? NYH5NVY4fGmvZTDk[ZBmdmSnboSg[IVkemWjc3WgbY4heHKxbHnm[ZJifGmxbjDy[YxifGm4ZTD0c{B1cGWrcjDEUXNQKHS{ZXH0[YQh[2:wdILvcJM> MlXEQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjZ2N{KxNFgoRjJ4NEeyNVA5RC:jPh?=
NB-EBc1 M3K4c5FJXFNiYYPzZZk> NVPqUmxQeUiWUzDv[kBx\WSrYYTybYMh[2GwY3XyJINmdGxibHnu[ZMhfG9iaXTlcpRq\nlibYXseIlxdGVib4Dwc5J1fW6rdHnld{Bnd3JiZIL1[{Bz\XC3coDvd4lv\zpiUILpcYFzgSC|Y4Ll[Y4h\m:{IF7CMWVD[zFiY3XscJM> M1jJbFxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEO1NVM6Lz5{OUSzOVE{QTxxYU6=
Assay
Methods Test Index 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 28369725 27729807 30049386
Immunofluorescence Vimentin / Phalloidin / Snail1 ; Rictor / Calnexin ; Fibrillarin ; LC3 ; γH2AX / 53BP1 / RPA / RAD51 ; chromosome / telomere ; F-actin / Aurora B 31068593 25089620 27729611 28211448 28369725
Growth inhibition assay Cell viability 26061708
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 Research:[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 Research:[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.

Solubility (25°C)

In vitro

Chemical Information

Molecular Weight 513.61
Formula

C27H27N7O2S

CAS No. 1138549-36-6
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC1=CN=C(C=N1)CNC(=O)C2=C3N(C4=CC=CC=C4S3)C5=C(C2=O)C=CC(=N5)N6CCCN(CC6)C

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Molarity Calculator

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02719977 Active not recruiting Drug: CX5461 Cancer Canadian Cancer Trials Group|Senhwa Biosciences Inc.|Stand Up To Cancer May 16 2016 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-08-01)

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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