RO4929097

Catalog No.S1575

RO4929097 Chemical Structure

Molecular Weight(MW): 469.4

RO4929097 is a γ secretase inhibitor with IC50 of 4 nM in a cell-free assay, inhibiting cellular processing of Aβ40 and Notch with EC50 of 14 nM and 5 nM, respectively. Phase 2.

Size Price Stock Quantity  
In DMSO USD 238 In stock
USD 170 In stock
USD 320 In stock
USD 970 In stock

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3 Customer Reviews

  • Stem Cells 2014 32(1), 301-12. RO4929097 purchased from Selleck.

    Stem Cells 2014 32(1), 301-12. RO4929097 purchased from Selleck.

  • Melanoma growth inhibition by the concomitant treatment with a TKI and the GSI inhibitor RO4929097. WM266-4, K457 and SK-Mel2 human metastatic melanoma cells were treated for four days in culture with a tyrosine kinase inhibitor (TKI at 20 mM), and the GSI RO4929097 (RO at 10 mM), either alone or in combination. All treatments significantly reduced cell growth except for RO4929097 on K457 cells. The highest level of inhibition was observed with TKI in combination with RO4929097. Growth was evaluated by the crystal violet staining.

     

     

    2012 Dr. Barbara Bedogni of Case Western Reserve University. RO4929097 purchased from Selleck.

Purity & Quality Control

Choose Selective Gamma-secretase Inhibitors

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Notes:

2. For more details, such as half maximal inhibitory concentrations (IC50s) and working concentrations of each inhibitor, please click on the link of the inhibitor of interest.
3. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation.
4. Orange "√" refers to compounds which do inhibitory effects on the related isoform, but without specific value.

Biological Activity

Description RO4929097 is a γ secretase inhibitor with IC50 of 4 nM in a cell-free assay, inhibiting cellular processing of Aβ40 and Notch with EC50 of 14 nM and 5 nM, respectively. Phase 2.
Targets
γ secretase [1]
(Cell-free assay)
γ secretase(ICN) [1]
(Cell-free assay)
Aβ40 [1]
(Cell-free assay)
4 nM 5 nM 14 nM
In vitro

RO4929097 decreases the amount of Aβ peptides secreted into the culture medium in HEK293 cells with EC50 of 14 nM. RO4929097 strongly inhibits Notch processing with EC50 of 5 nM in the Notch cell-based reporter assay. The potency of RO4929097 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity observed with respect to 75 other proteins of various types including receptors, ion channels, and enzymes (CEREP panel). After 5 days of treatment, RO4929097 reduces the production of ICN in the human NSCLC A549 cells inducing a flattened and less transformed tumor cell phenotype in tissue culture. [1] RO4929097 blocks Notch processing in human non-small cell lung carcinoma cells and decreases expression of the Notch transcriptional target gene Hes1. Treatment with RO4929097 reveals a two- to threefold decrease in the expression of direct Notch target genes, Hes1, Hey1, and Heyl in SUM149 and a 3.5- to eightfold decrease in expression in SUM190 cells. RO4929097 modestly inhibits the growth of SUM149 cells in a dose-dependent manner. At a concentration of 1 μM of RO4929097, growth inhibition is 20 % for SUM149 and 10 % for SUM190 cells, relative to vehicle-treated controls. RO4929097 decreases the production of inflammatory cytokines by T-cells. Furthermore, with RO4929097 treatment, there is a shift in favor of TH2 over TH1 cytokines. In addition, T-cell activation induced IL-6 production would be increased with RO4929097. [2] Upon RO4929097 treatment, the selected melanoma cell lines reveals downregulation of NOTCH downstream effector HES1. A decrease in the amount of melanospheres formed upon RO4929097 treatment in primary melanoma cell lines is detected. [3]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
U87 NHP3S49E\WyuIG\pZYJqdGm2eTDBd5NigQ>? MUmzNEDPxE1? MlWyOEBl NWLh[Flv\GWlcnXhd4V{KGOnbHygeoli[mmuaYT5 MkXDNlQ1QTV7MEe=
U87 R1 M3iyXGNmdGxiVnnhZoltcXS7IFHzd4F6 MonFN|Ah|ryP NV\qWnV6PCCm NYXxSWY2\GWlcnXhd4V{KGOnbHygeoli[mmuaYT5 M3e1UlI1PDl3OUC3
MGG4 M3;tbmNmdGxiVnnhZoltcXS7IFHzd4F6 M1\DblMxKM7:TR?= MoDzOEBl MYDk[YNz\WG|ZYOgZ4VtdCC4aXHibYxqfHl? MXuyOFQ6PTlyNx?=
MGG6 MonsR4VtdCCYaXHibYxqfHliQYPzZZk> Mn;oN|Ah|ryP NHLOcGQ1KGR? Ml3p[IVkemWjc3XzJINmdGxidnnhZoltcXS7 MlPhNlQ1QTV7MEe=
MGG8 MorIR4VtdCCYaXHibYxqfHliQYPzZZk> Mnq4N|Ah|ryP MWq0JIQ> MnKy[IVkemWjc3XzJINmdGxidnnhZoltcXS7 MoiwNlQ1QTV7MEe=
MGG23 MY\D[YxtKF[rYXLpcIl1gSCDc4PhfS=> NVf4SJVkOzBizszN MkTlOEBl Monn[IVkemWjc3XzJINmdGxidnnhZoltcXS7 MVmyOFQ6PTlyNx?=
SUM149 MnHaR4VtdCCYaXHibYxqfHliQYPzZZk> NVTHbmZEOC1zMDFOwG0> MUO3NkBp Ml;jbY5pcWKrdIOgZ4VtdCCpcn;3eIgh\G:|ZTDk[ZBmdmSnboTsfS=> MWqyNlU1PzFyOR?=
Sum190 NHPBeXNE\WyuIG\pZYJqdGm2eTDBd5NigQ>? MYqwMVExKM7:TR?= MXu3NkBp MW\pcohq[mm2czDj[YxtKGe{b4f0bEBld3OnIHTldIVv\GWwdHz5 NV\lfopnOjJ3NEexNFk>
WM35 NWrycGpuTnWwY4Tpc44hSXO|YYm= NW\FOllmOTBidV2= NGLKSGYzPCCq MWfEUXNQ M3;J[4Rm[3KnYYPld{B1cGVibHX2[Yx{KG:oIF7PWGNJKGSxd37zeJJm[W1idHHy[4V1KEiHU{G= NH:zZ5EzOTl6MESwPC=>
WM98.1 MUPGeY5kfGmxbjDBd5NigQ>? NYjOWJF[OTBidV2= NXXpUFBnOjRiaB?= NGnzSI1FVVOR NVXZWYpJ\GWlcnXhd4V{KHSqZTDs[ZZmdHNib3[gUm9VS0hiZH;3cpN1emWjbTD0ZZJo\XRiSFXTNS=> MWeyNVk5ODRyOB?=
WM115 M{HWUWZ2dmO2aX;uJGF{e2G7 NFmyV5kyOCC3TR?= NVrKeJR6OjRiaB?= NV3qcJN7TE2VTx?= MlWx[IVkemWjc3XzJJRp\SCuZY\lcJMhd2ZiTl;UR2gh\G:5boP0doVidSC2YYLn[ZQhUEWVMR?= MYGyNVk5ODRyOB?=
WM983A Mn7wSpVv[3Srb36gRZN{[Xl? MoqxNVAhfU1? NYfGVG5qOjRiaB?= MV;EUXNQ NGLjdIVl\WO{ZXHz[ZMhfGinIHzleoVteyCxZjDOU3REUCCmb4fud5Rz\WGvIIThdodmfCCKRWOx MonVNlE6QDB2MEi=
WM3248  NHntXYhHfW6ldHnvckBCe3OjeR?= Mlr3NVAhfU1? MVeyOEBp NX7Tc5gzTE2VTx?= MmnC[IVkemWjc3XzJJRp\SCuZY\lcJMhd2ZiTl;UR2gh\G:5boP0doVidSC2YYLn[ZQhUEWVMR?= NEjjV4szOTl6MESwPC=>
WM35 M3T3bmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIfRXY4yOCC3TR?= M4P4d|AuOThiZB?= MXLEUXNQ MX7pcohq[mm2czDj[YxtKGe{b4f0bEB1cW2nIHTldIVv\GWwdHz5 NWn4RllSOjF7OEC0NFg>
WM98.1 NHj4dXlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXuxNEB2VQ>? NV\5NXdqOC1zODDk MV3EUXNQ NFrYNoxqdmirYnn0d{Bk\WyuIHfyc5d1cCC2aX3lJIRmeGWwZHXueIx6 MVSyNVk5ODRyOB?=
WM115 NFr4PHdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NImyPXYyOCC3TR?= MUewMVE5KGR? NGDuelVFVVOR MY\pcohq[mm2czDj[YxtKGe{b4f0bEB1cW2nIHTldIVv\GWwdHz5 MVWyNVk5ODRyOB?=
WM983A MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Ml3xNVAhfU1? NVXsT2ZROC1zODDk MXPEUXNQ MUDpcohq[mm2czDj[YxtKGe{b4f0bEB1cW2nIHTldIVv\GWwdHz5 M2rh[VIyQThyNEC4
WM3248  NIDzb4FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHzNRmoyOCC3TR?= MUCwMVE5KGR? NX;hRVNrTE2VTx?= NWHo[4E1cW6qaXLpeJMh[2WubDDndo94fGhidHnt[UBl\XCnbnTlcpRtgQ>? NUexTYZPOjF7OEC0NFg>

... Click to View More Cell Line Experimental Data

In vivo Oral injection of 3 to 60 mg/kg RO4929097 once daily or twice daily to nude mice bearing A549 NSCLC xenografts for either 7, 14, or 21 days of a 21-day schedule results in significant tumor growth inhibition compared with vehicle-treated animals. The tumor growth inhibition values ranges from 66% to 91%. When mice are treated with 60 mg/kg RO4929097 twice daily with the 7+/14- schedule, treatment initially arouses regression of established A549 tumors. At the end of the 21-day cycle (day 47), tumor growth prevention is still 91% compared with vehicle control mice. Inhibition of tumor growth remains prolonged and sustained up to 34 days post-treatment (day 67). On day 67, these mice are retreated with the same dose of RO4929097 for a second cycle (7 days) until day 74. Importantly, the antitumor effects are sustained after dosing is completed. [1] RO4929097 leads to reduced expression of genes associated with angiogenesis in A549 xenograft model. In contrast, the RO4929097-resistant H460a xenograft displays little change in expression of these genes, underscoring the in vivo anti-angiogenesis mechanism of action of RO4929097.[2] For IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. [4]

Protocol

Kinase Assay:[5]
+ Expand

In vitro potency assays:

After RO4929097 is used, the Aβ peptides are measured by ECL assays using a variety of anti-Aβ antibodies and an Origen 1.5 Analyzer. The 4G8 murine mAb binds an epitope in the Aβ peptide (within amino acids 18–21) that is immediately distal to the α-secretase cleavage site. The G2–10 murine mAb binds the C terminus that is exposed after γ-secretase-mediated cleavage to generate amino acid 40 of the Aβ40 peptide. The FCA3542 rabbit antibody binds the C terminus that is exposed after γ-secretase-mediated cleavage to generate amino acid 42 of the Aβ42 peptide. The 4G8 mAb is biotinylated with biotin-LC-sulfo-N-hydroxysuccinimide-ester. The G2–10 and FCA3542 antibodies are ruthenylated with TAG-N-hydroxysuccinimide ester. Aβ(x-40) is detected with biotinylated 4G8 and ruthenylated G2–10. Aβ(x-42) is detected with biotinylated 4G8 and ruthenylated FCA3542.
Cell Research:[3]
+ Expand
  • Cell lines: WM35 and WM98.1 cell lines
  • Concentrations: 10 μM
  • Incubation Time: DMSO
  • Method: Primary melanoma cell lines, including WM35 and WM98.1, are seeded at 2.5 × 103 cells per well on a 12-well dish in triplicate. The day after (day 0), the medium is replaced, and DMSO or 10 μM RO4929097 is added and changed every 3-4 days. At the indicated time points, cells are fixed in 10% formalin solution and stored in PBS at 4 °C. At day 18-24, all the plates are stained with crystal violet. After color elution with 10% acetic acid, optical density is read at 590 nm.
    (Only for Reference)
Animal Research:[1]
+ Expand
  • Animal Models: Female nude mice bearing Calu-6 cells
  • Formulation: 1.0% Klucel in water with 0.2% Tween 80
  • Dosages: 3 to 60 mg/kg
  • Administration: Oral administration
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 94 mg/mL (200.25 mM)
Ethanol 16 mg/mL (34.08 mM)
Water <1 mg/mL
In vivo 2% DMSO+30% PEG 300+5% Tween+ddH2O 10mg/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 Information

Molecular Weight 469.4
Formula

C22H20F5N3O3

CAS No. 847925-91-1
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01236586 Withdrawn Lymphoma|Brain Neoplasms|Sarcoma|Osteosarcoma|Wilms Tumor National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) October 8, 2010 Phase 1
NCT01269411 Terminated Adult Anaplastic Oligodendroglioma|Adult Brain Stem Glioma|Adult Giant Cell Glioblastoma|Adult Glioblastoma|Adult Gliosarcoma|Adult Mixed Glioma|Recurrent Adult Brain Tumor National Cancer Institute (NCI) July 2011 Phase 1
NCT01270438 Withdrawn Adenocarcinoma of the Colon|Adenocarcinoma of the Rectum|Recurrent Colon Cancer|Recurrent Rectal Cancer|Stage IVA Colon Cancer|Stage IVA Rectal Cancer|Stage IVB Colon Cancer|Stage IVB Rectal Cancer National Cancer Institute (NCI) December 2010 Phase 2
NCT01189240 Terminated Adult Anaplastic Astrocytoma|Adult Anaplastic Oligodendroglioma|Adult Giant Cell Glioblastoma|Adult Glioblastoma|Adult Gliosarcoma|Recurrent Adult Brain Tumor National Cancer Institute (NCI) December 2010 Phase 1|Phase 2
NCT01238133 Terminated Estrogen Receptor Negative|HER2/Neu Negative|Progesterone Receptor Negative|Stage IIA Breast Cancer|Stage IIB Breast Cancer|Stage IIIA Breast Cancer|Stage IIIB Breast Cancer|Stage IIIC Breast Cancer|Triple-Negative Breast Carcinoma National Cancer Institute (NCI) December 2010 Phase 1
NCT01122901 Active, not recruiting Adult Giant Cell Glioblastoma|Adult Glioblastoma|Adult Gliosarcoma|Recurrent Adult Brain Tumor National Cancer Institute (NCI) December 2010 Phase 2

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID