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.

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In DMSO USD 238 In stock
USD 170 In stock
USD 320 In stock
USD 970 In stock
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Cited by 29 Publications

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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 M3La[mNmdGxiVnnhZoltcXS7IFHzd4F6 NGC5R4o{OCEQvF2= MnPQOEBl M37M[YRm[3KnYYPld{Bk\WyuII\pZYJqdGm2eR?= M1Lud|I1PDl3OUC3
U87 R1 NUjlfoxUS2WubDDWbYFjcWyrdImgRZN{[Xl? MkDnN|Ah|ryP MYG0JIQ> NVrEOZJJ\GWlcnXhd4V{KGOnbHygeoli[mmuaYT5 M1roW|I1PDl3OUC3
MGG4 NWPITGM2S2WubDDWbYFjcWyrdImgRZN{[Xl? NYDBUW9POzBizszN M37DN|Qh\A>? M3f1NIRm[3KnYYPld{Bk\WyuII\pZYJqdGm2eR?= NH\HbYwzPDR7NUmwOy=>
MGG6 M3vDbmNmdGxiVnnhZoltcXS7IFHzd4F6 M3T3VlMxKM7:TR?= NGPUWWk1KGR? NH7C[IJl\WO{ZXHz[ZMh[2WubDD2bYFjcWyrdIm= NG\mUXczPDR7NUmwOy=>
MGG8 MlTTR4VtdCCYaXHibYxqfHliQYPzZZk> M3nFdlMxKM7:TR?= Ml;0OEBl NF3iWJFl\WO{ZXHz[ZMh[2WubDD2bYFjcWyrdIm= MXqyOFQ6PTlyNx?=
MGG23 M4rESWNmdGxiVnnhZoltcXS7IFHzd4F6 M3jO[|MxKM7:TR?= NVHpdJFsPCCm MmPG[IVkemWjc3XzJINmdGxidnnhZoltcXS7 MUOyOFQ6PTlyNx?=
SUM149 M2XIVmNmdGxiVnnhZoltcXS7IFHzd4F6 Mn3NNE0yOCEQvF2= MlrBO|IhcA>? NX6weo5{cW6qaXLpeJMh[2WubDDndo94fGhiZH;z[UBl\XCnbnTlcpRtgQ>? NYfON2JTOjJ3NEexNFk>
Sum190 NYfMXHNiS2WubDDWbYFjcWyrdImgRZN{[Xl? MkLGNE0yOCEQvF2= MWK3NkBp M3TKWIlvcGmkaYTzJINmdGxiZ4Lve5RpKGSxc3Wg[IVx\W6mZX70cJk> MX[yNlU1PzFyOR?=
WM35 NWHufnJPTnWwY4Tpc44hSXO|YYm= NF[2VpAyOCC3TR?= NHP1Tm8zPCCq M37kZ2ROW09? Mnju[IVkemWjc3XzJJRp\SCuZY\lcJMhd2ZiTl;UR2gh\G:5boP0doVidSC2YYLn[ZQhUEWVMR?= M3[3flIyQThyNEC4
WM98.1 NYPNRpdUTnWwY4Tpc44hSXO|YYm= NF3oV4QyOCC3TR?= M1vyZ|I1KGh? MWfEUXNQ M3m1WIRm[3KnYYPld{B1cGVibHX2[Yx{KG:oIF7PWGNJKGSxd37zeJJm[W1idHHy[4V1KEiHU{G= MXSyNVk5ODRyOB?=
WM115 NHnEVGhHfW6ldHnvckBCe3OjeR?= MYixNEB2VQ>? NFzHUlAzPCCq NF[4ZZNFVVOR MlX4[IVkemWjc3XzJJRp\SCuZY\lcJMhd2ZiTl;UR2gh\G:5boP0doVidSC2YYLn[ZQhUEWVMR?= M3y3e|IyQThyNEC4
WM983A MV\GeY5kfGmxbjDBd5NigQ>? NXn5XIQxOTBidV2= NWThOHdQOjRiaB?= NEGxfHBFVVOR NYDUNnox\GWlcnXhd4V{KHSqZTDs[ZZmdHNib3[gUm9VS0hiZH;3cpN1emWjbTD0ZZJo\XRiSFXTNS=> NGHxZZczOTl6MESwPC=>
WM3248  MYPGeY5kfGmxbjDBd5NigQ>? NEfDZm0yOCC3TR?= M{P5SVI1KGh? NXThco1DTE2VTx?= NH3zVnpl\WO{ZXHz[ZMhfGinIHzleoVteyCxZjDOU3REUCCmb4fud5Rz\WGvIIThdodmfCCKRWOx NGPBZZozOTl6MESwPC=>
WM35 M3nvXWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mmq3NVAhfU1? M1;1TlAuOThiZB?= MXPEUXNQ NYT4OoU5cW6qaXLpeJMh[2WubDDndo94fGhidHnt[UBl\XCnbnTlcpRtgQ>? NGW4eogzOTl6MESwPC=>
WM98.1 NVjVbZg4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MX[xNEB2VQ>? NFXOTI8xNTF6IHS= NYH6VoV7TE2VTx?= M2jnUolvcGmkaYTzJINmdGxiZ4Lve5RpKHSrbXWg[IVx\W6mZX70cJk> M4DI[|IyQThyNEC4
WM115 M{PJe2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUWxNEB2VQ>? NYX4RZlCOC1zODDk NUDKXlJ5TE2VTx?= M{DwVolvcGmkaYTzJINmdGxiZ4Lve5RpKHSrbXWg[IVx\W6mZX70cJk> MWqyNVk5ODRyOB?=
WM983A NFPzNWtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NIPxcJMyOCC3TR?= MWSwMVE5KGR? MlvFSG1UVw>? MYXpcohq[mm2czDj[YxtKGe{b4f0bEB1cW2nIHTldIVv\GWwdHz5 MWiyNVk5ODRyOB?=
WM3248  MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mlu5NVAhfU1? M3HBVVAuOThiZB?= MWrEUXNQ NGj2UGJqdmirYnn0d{Bk\WyuIHfyc5d1cCC2aX3lJIRmeGWwZHXueIx6 M{Hu[VIyQThyNEC4

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
Hey1; 

PubMed: 29899322     


HeLa and Caski cells treated with RO4929097 and the DMSO control showed downregulation of the Hey1 protein as determined by Western blot analysis;

Snail / N-cadherin / Twist / E-cadherin; 

PubMed: 29899322     


Effect of inhibiting the Notch signaling pathway on the protein expression levels of EMT-associated proteins Snail, N-cadherin, Twist, and E-cadherin in HeLa and Caski cells. 

Akt / p-Akt / Notch / IGF1R / FBXW7 ; 

PubMed: 28507201     


Western blots showing expression of p-Akt, Akt, Notch, IGF1R, and FBXW7 in HCC827/ER cells treated with MK-2206 (an Akt inhibitor) or RO4929097 (a Notch inhibitor). GAPDH served as an internal control. 

NICD / Hes1 / Hes3 / Hes5; 

PubMed: 24038660     


A panel of GICs was treated with the indicated doses of DAPT, BMS-708163 and RO4929097 for 48 hours. γ Secretase inhibitors inhibited expression of NICD, Hes1, Hes3 and Hes5 in a dose-dependent manner.

29899322 28507201 24038660
Growth inhibition assay
Cell viability; 

PubMed: 30669546     


A panel of GIC lines was treated with various concentrations of the RO4929097. Cells were treated in triplicate wells for 72 h, and cell viability was assessed with the CellTiter-Blue assay. Cell viability in the vehicle control was considered to be 100%; 

30669546
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 93 mg/mL (198.12 mM)
Ethanol 16 mg/mL (34.08 mM)
Water Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+30% PEG 300+5% Tween+ddH2O
For best results, use promptly after mixing.
10mg/mL

* 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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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.

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Frequently Asked Questions

  • Question 1:

    How about the half-life of RO4929097(S1575)?

  • Answer:

    For S1575, the half-life is about 20 hours based on the following paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869895/

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID