Rigosertib (ON-01910)

Catalog No.S1362

Rigosertib (ON-01910) is a non-ATP-competitive inhibitor of PLK1 with IC50 of 9 nM in a cell-free assay. It shows 30-fold greater selectivity against Plk2 and no activity to Plk3. Phase 3.

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Rigosertib (ON-01910) Chemical Structure

Rigosertib (ON-01910) Chemical Structure
Molecular Weight: 473.47

Validation & Quality Control

3 customer reviews :

Quality Control & MSDS

Related Compound Libraries

Rigosertib (ON-01910) is available in the following compound libraries:

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Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description Rigosertib (ON-01910) is a non-ATP-competitive inhibitor of PLK1 with IC50 of 9 nM in a cell-free assay. It shows 30-fold greater selectivity against Plk2 and no activity to Plk3. Phase 3.
Targets PLK1 [1]
(Cell-free assay)
IC50 9 nM
In vitro Rigosertib is non-ATP-competitive inhibitor to PLK1 with IC50 of 9 nM. Rigosertib also exhibits inhibition against PLK2, PDGFR, Flt1, BCR-ABL, Fyn, Src, and CDK1, with IC50 of 18-260 nM. Rigosertib shows cell killing activity against 94 different tumor cell lines with IC50 of 50-250 nM, including BT27, MCF-7, DU145, PC3, U87, A549, H187, RF1, HCT15, SW480, and KB cells. While in normal cells, such as HFL, PrEC, HMEC, and HUVEC, Rigosertib has little or no effect unless its concentration is greater than 5-10 μM. In HeLa cells, Rigosertib (100-250 nM) induces spindle abnormalities and apoptosis. [1] Rigosertib also inhibits several multidrug resistant tumor cell lines, including MES-SA, MES-SA/DX5a, CEM, and CEM/C2a, with IC50 of 50-100 nM. In DU145 cells, Rigosertib (0.25-5 μM) blocks cell cycle progression in G2/M phase, results in an accumulation of cells containing subG1 content of DNA, and activates apoptotic pathways. In A549 cells, Rigosertib (50 nM-0.5 μM) induces loss of viability and caspase 3/7 activation. [2] In a recent study, Rigosertib induces apoptosis in chronic lymphocytic leukemia (CLL) cells without toxicity against T-cells or normal B-cells. Rigosertib also abrogates the pro-survival effect of follicular dendritic cells on CLL cells and reduces SDF-1-induced migration of leukemic cells. [3]
In vivo In mouse xenograft models of Bel-7402, MCF-7, and MIA-PaCa cells, Rigosertib (250 mg/kg) markedly inhibits tumor growth. [1] Rigosertib (200 mg/kg) shows inhibition on tumor growth in a mouse xengraft model of BT20 cells. [2]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

In vitro enzyme assays for PLK1 Recombinant PLK1 (10 ng) is incubated with different concentrations of Rigosertib in a 15 µL reaction mixture (50 mM HEPES, 10 mM MgCl2, 1 mM EDTA, 2 mM Dithiothreitol, 0.01% NP-40 [pH 7.5]) for 30 min at room temperature. Kinase reactions are performed for 20 min at 30 °C in a volume of 20 µL (15 µL enzyme + inhibitor, 2 µL 1 mM ATP), 2 µL of γ32P-ATP (40 μCi), and 1 µL of recombinant Cdc25C (100 ng) or casein (1 μg) substrates. Reactions are terminated by boiling for 2 min in 20 µL of 2× Laemmli buffer. Phosphorylated substrates are separated by 18% SDS-PAGE. The gels are dried and exposed to X-ray film for 3-10 min.

Cell Assay: [2]

Cell lines A number of tumor cell lines, including BT20, MCF-7, DU145, PC3, U87, A549, H187, RF1, HCT15, HeLa, and Raji cells
Concentrations 1 nM - 10 μM, dissolved in DMSO as stock solution.
Incubation Time 96 hours
Method Cells are grown in either DMEM or RPMI supplemented with 10% fetal bovine serum and 1 unit/mL penicillin-streptomycin solution. Tumor cells are plated into six-well dishes at a density of 1 × 105cells/mL/well, and Rigosertib is added 24 hours later at various concentrations. Cell counts are determined from duplicate wells after 96-hour of treatment. The total number of viable cells is determined by trypan blue exclusio

Animal Study: [1]

Animal Models Mouse (female athymic, NCR-nu/nu) xenograft models of Bel-7402, MCF-7, and MIA-PaCa cells
Formulation Dissolved in PBS
Dosages 250 mg/kg
Administration Intraperitonially

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Gumireddy K, et al. Cancer Cell, 2005, 7(3), 275-286.

[2] Reddy MV, et al. J Med Chem, 2011, 54(18), 6254-6276.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02730884 Not yet recruiting Leukemia|Myelofibrosis|Anemia|Splenomegaly M.D. Anderson Cancer Center|Onconova Therapeutics, Inc. June 2016 Phase 2
NCT02562443 Recruiting Myelodysplastic Syndrome|MDS|Refractory Anemia With Excess Blasts|RAEB Onconova Therapeutics, Inc. October 2015 Phase 3
NCT02075034 Suspended Myelodysplastic Syndrome Onconova Therapeutics, Inc. May 2014 Phase 1
NCT02030639 Completed Healthy Onconova Therapeutics, Inc. January 2014 Phase 1
NCT02107235 Completed Head and Neck Neoplasms|Carcinoma, Squamous Cell Onconova Therapeutics, Inc. January 2014 Phase 1

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Chemical Information

Download Rigosertib (ON-01910) SDF
Molecular Weight (MW) 473.47
Formula

C21H24NNaO8S

CAS No. 1225497-78-8
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 95 mg/mL (200.64 mM)
Water 95 mg/mL (200.64 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo Saline 30 mg/mL
* <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.
Chemical Name N-​[2-​methoxy-​5-​[[[2-​(2,​4,​6-​trimethoxyphenyl)​ethenyl]​sulfonyl]​methyl]​phenyl]​-​glycine,sodium salt (1:1)

Customer Product Validation(3)


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Rating
Source PLoS One 2013 8(11), e79863. Rigosertib (ON-01910) purchased from Selleck
Method Western blot
Cell Lines LCL, HT, SU-DHL-5 cells
Concentrations 0-0.5 uM
Incubation Time
Results Along with cell death, immunoblotting demonstrated that ON 01910.Na induced hyperphosphorylation of RanGAP1, increased expression of RanGAP1.SUMO1 but decreased expression of free unmodified RanGAP1.

Click to enlarge
Rating
Source Rigosertib (ON-01910) purchased from Selleck
Method MTT Assay
Cell Lines leukemia cell lines
Concentrations 0.001-1 μM
Incubation Time 48 h
Results ON01910 demonstrated a good capacity to inhibit leukemia cell growth in a concentration dependent manner.

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Rating
Source Dr. Antonino Maria Sparta, PhD University of Bologna. Rigosertib (ON-01910) purchased from Selleck
Method Western Blot
Cell Lines Jurkat E6.1 Cells
Concentrations 500 nM
Incubation Time 48 h
Results Both CCT137690 and ON01910 were significantly able to reduce the phosphorylation states of the centrosomal protein TACC3 and of the histone H3, which are known targets of Aurora kinases.

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