RO4929097

Catalog No.S1575 Synonyms: RG-4733

For research use only.

RO4929097 (RG-4733) 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.

RO4929097 Chemical Structure

CAS No. 847925-91-1

Selleck's RO4929097 has been cited by 105 publications

Purity & Quality Control

Choose Selective Secretase Inhibitors

Biological Activity

Description RO4929097 (RG-4733) 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
Secretase [1]
(Cell-free assay)
Notch [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 M2fmdmNmdGxiVnnhZoltcXS7IFHzd4F6 MnzMN|Ah|ryP NIjad3g1KGR? MmfQ[IVkemWjc3XzJINmdGxidnnhZoltcXS7 NXu4SJJYRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkS0PVU6ODdpPkK0OFk2QTB5PD;hQi=>
U87 R1 MkT4R4VtdCCYaXHibYxqfHliQYPzZZk> MUCzNEDPxE1? M1zpRVQh\A>? MUPk[YNz\WG|ZYOgZ4VtdCC4aXHibYxqfHl? MVi8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDR7NUmwO{c,OjR2OUW5NFc9N2F-
MGG4 M1LQfWNmdGxiVnnhZoltcXS7IFHzd4F6 M{j4V|MxKM7:TR?= MX60JIQ> MVrk[YNz\WG|ZYOgZ4VtdCC4aXHibYxqfHl? MYe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPDR7NUmwO{c,OjR2OUW5NFc9N2F-
MGG6 M1LRS2NmdGxiVnnhZoltcXS7IFHzd4F6 MUizNEDPxE1? NGTQVnA1KGR? MV;k[YNz\WG|ZYOgZ4VtdCC4aXHibYxqfHl? NH7aW|A9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NES5OVkxPyd-MkS0PVU6ODd:L3G+
MGG8 MmrYR4VtdCCYaXHibYxqfHliQYPzZZk> Mlr5N|Ah|ryP NHjvbJg1KGR? NGPhN2Vl\WO{ZXHz[ZMh[2WubDD2bYFjcWyrdIm= NIXFdY49[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{NES5OVkxPyd-MkS0PVU6ODd:L3G+
MGG23 MkewR4VtdCCYaXHibYxqfHliQYPzZZk> NHn5bWU{OCEQvF2= M3LFSFQh\A>? NGH4VFFl\WO{ZXHz[ZMh[2WubDD2bYFjcWyrdIm= MlL4QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjR2OUW5NFcoRjJ2NEm1PVA4RC:jPh?=
SUM149 NXfp[4RzS2WubDDWbYFjcWyrdImgRZN{[Xl? M3TxfFAuOTBizszN M4PScVczKGh? MX;pcohq[mm2czDj[YxtKGe{b4f0bEBld3OnIHTldIVv\GWwdHz5 MV28ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOjV2N{GwPUc,OjJ3NEexNFk9N2F-
Sum190 MkLOR4VtdCCYaXHibYxqfHliQYPzZZk> MWiwMVExKM7:TR?= MX23NkBp M2HGUolvcGmkaYTzJINmdGxiZ4Lve5RpKGSxc3Wg[IVx\W6mZX70cJk> NFzOXHA9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{MkW0O|ExQSd-MkK1OFcyODl:L3G+
WM35 M2jmU2Z2dmO2aX;uJGF{e2G7 NWjySGVLOTBidV2= M4\NOVI1KGh? MV\EUXNQ NWTGW4Jq\GWlcnXhd4V{KHSqZTDs[ZZmdHNib3[gUm9VS0hiZH;3cpN1emWjbTD0ZZJo\XRiSFXTNS=> MWS8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOTl6MESwPEc,OjF7OEC0NFg9N2F-
WM98.1 NYfuXm02TnWwY4Tpc44hSXO|YYm= MmS5NVAhfU1? MkjXNlQhcA>? Ml7MSG1UVw>? M2GyV4Rm[3KnYYPld{B1cGVibHX2[Yx{KG:oIF7PWGNJKGSxd37zeJJm[W1idHHy[4V1KEiHU{G= MUi8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOTl6MESwPEc,OjF7OEC0NFg9N2F-
WM115 NFjzW|FHfW6ldHnvckBCe3OjeR?= Mn\ENVAhfU1? MoDaNlQhcA>? MWHEUXNQ MmfG[IVkemWjc3XzJJRp\SCuZY\lcJMhd2ZiTl;UR2gh\G:5boP0doVidSC2YYLn[ZQhUEWVMR?= MkCwQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjF7OEC0NFgoRjJzOUiwOFA5RC:jPh?=
WM983A M4HieWZ2dmO2aX;uJGF{e2G7 NH62WYUyOCC3TR?= MmjaNlQhcA>? NGrM[I1FVVOR NF:4Sm1l\WO{ZXHz[ZMhfGinIHzleoVteyCxZjDOU3REUCCmb4fud5Rz\WGvIIThdodmfCCKRWOx MmnVQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjF7OEC0NFgoRjJzOUiwOFA5RC:jPh?=
WM3248  MXPGeY5kfGmxbjDBd5NigQ>? NV3GbHQ6OTBidV2= MmnGNlQhcA>? NXrjSGJZTE2VTx?= M{i5eIRm[3KnYYPld{B1cGVibHX2[Yx{KG:oIF7PWGNJKGSxd37zeJJm[W1idHHy[4V1KEiHU{G= NEnST|Y9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{MUm4NFQxQCd-MkG5PFA1ODh:L3G+
WM35 MVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MoXJNVAhfU1? NHm2SpUxNTF6IHS= M3jKW2ROW09? Mof1bY5pcWKrdIOgZ4VtdCCpcn;3eIghfGmvZTDk[ZBmdmSnboTsfS=> M1KzclxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJzOUiwOFA5Lz5{MUm4NFQxQDxxYU6=
WM98.1 M2m3UWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MkThNVAhfU1? NX7Gc5A2OC1zODDk MmfiSG1UVw>? NXX0e29IcW6qaXLpeJMh[2WubDDndo94fGhidHnt[UBl\XCnbnTlcpRtgQ>? NUHZV3pzRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkG5PFA1ODhpPkKxPVgxPDB6PD;hQi=>
WM115 NEH3XVhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NX\ucoJHOTBidV2= Mmj3NE0yQCCm MWfEUXNQ NUHlcohDcW6qaXLpeJMh[2WubDDndo94fGhidHnt[UBl\XCnbnTlcpRtgQ>? M1\PWlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJzOUiwOFA5Lz5{MUm4NFQxQDxxYU6=
WM983A MX;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXnrXGJHOTBidV2= MWKwMVE5KGR? NFnQUm9FVVOR MmDBbY5pcWKrdIOgZ4VtdCCpcn;3eIghfGmvZTDk[ZBmdmSnboTsfS=> NYXI[lVDRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkG5PFA1ODhpPkKxPVgxPDB6PD;hQi=>
WM3248  NIm2SY5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkSxNVAhfU1? NXXm[3hzOC1zODDk NHPDNHNFVVOR M1znNolvcGmkaYTzJINmdGxiZ4Lve5RpKHSrbXWg[IVx\W6mZX70cJk> NG\4NYg9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{MUm4NFQxQCd-MkG5PFA1ODh:L3G+
A673 M4fIfZFJXFNiYYPzZZk> MVK8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR|NUGzPUc,Ojl2M{WxN|k9N2F-
DAOY NFmxeG5yUFSVIHHzd4F6 NGfwTIo9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N|UyOzl:L3G+
BT-37 NHT4c4dyUFSVIHHzd4F6 NIjlV4I9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N|UyOzl:L3G+
BT-12 NVzEV3dMeUiWUzDhd5NigQ>? M1\USVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEO1NVM6Lz5{OUSzOVE{QTxxYU6=
OHS-50 M2X1b5FJXFNiYYPzZZk> MVm8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR|NUGzPUc,Ojl2M{WxN|k9N2F-
SJ-GBM2 NFLOSYdyUFSVIHHzd4F6 Mn7HQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2M{WxN|koRjJ7NEO1NVM6RC:jPh?=
SK-N-MC MWnxTHRUKGG|c3H5 M17vRlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEO1NVM6Lz5{OUSzOVE{QTxxYU6=
NB-EBc1 M4iwSJFJXFNiYYPzZZk> M4HHbVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEO1NVM6Lz5{OUSzOVE{QTxxYU6=
LAN-5 NFX6ZWxyUFSVIHHzd4F6 NUOzblJVRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkm0N|UyOzlpPkK5OFM2OTN7PD;hQi=>
Assay
Methods Test Index PMID
Western blot Hey1 ; Snail / N-cadherin / Twist / E-cadherin ; Akt / p-Akt / Notch / IGF1R / FBXW7 ; NICD / Hes1 / Hes3 / Hes5 29899322 28507201 24038660
Growth inhibition assay Cell viability 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 (from reference)

Kinase Assay:[5]
  • 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]
  • 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.
Animal Research:[1]
  • Animal Models: Female nude mice bearing Calu-6 cells
  • Dosages: 3 to 60 mg/kg
  • Administration: Oral administration

Solubility (25°C)

In vitro

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

Chemical Information

Molecular Weight 469.4
Formula

C22H20F5N3O3

CAS No. 847925-91-1
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC(C)(C(=O)NCC(C(F)(F)F)(F)F)C(=O)NC1C2=CC=CC=C2C3=CC=CC=C3NC1=O

In vivo Formulation Calculator (Clear solution)

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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

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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:
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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