RO4929097

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

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RO4929097 Chemical Structure

RO4929097 Chemical Structure
Molecular Weight: 469.4

Validation & Quality Control

Customer Reviews(3)

Quality Control & MSDS

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Product Description

Biological Activity

Description RO4929097 is a γ secretase inhibitor with IC50 of 4 nM, inhibiting cellular processing of Aβ40 and Notch with EC50 of 14 nM and 5 nM, respectively. Phase 2.
Targets γ secretase [1] γ secretase(ICN) [1] γ secretase(Aβ40) [1]
IC50 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]
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]
Features

Protocol(Only for 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 Assay: [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 Study: [1]

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
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, 15 mg/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.

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

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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] Luistro L, et al. Cancer Res. 2009, 69(19), 7672-7680.

[2] Debeb BG, et al. Breast Cancer Res Treat. 2012.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-20)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01269411 Terminated Adult Anaplastic Oligodendroglioma|Adult Brain Stem Glioma|Adult Giant Cell Glioblastoma|Adult Glioblastoma|Adult Gliosarcoma|Adult Mixed Glioma|Re  ...more 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
NCT01238133 Active, not recruiting Estrogen Receptor-negative Breast Cancer|HER2-negative Breast Cancer|Male Breast Cancer|Progesterone Receptor-negative Breast Cancer|Stage II Breas  ...more Estrogen Receptor-negative Breast Cancer|HER2-negative Breast Cancer|Male Breast Cancer|Progesterone Receptor-negative Breast Cancer|Stage II Breast Cancer|Stage IIIA Breast Cancer|Stage IIIB Breast Cancer|Stage IIIC Breast Cancer|Triple-negative Breast Cancer 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
NCT01251172 Withdrawn Refractory Multiple Myeloma|Stage I Multiple Myeloma|Stage II Multiple Myeloma|Stage III Multiple Myeloma National Cancer Institute (NCI) December 2010 Phase 2
NCT01270438 Withdrawn Adenocarcinoma of the Colon|Adenocarcinoma of the Rectum|Recurrent Colon Cancer|Recurrent Rectal Cancer|Stage IVA Colon Cancer|Stage IVA Rectal Can  ...more 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

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Chemical Information

Download RO4929097 SDF
Molecular Weight (MW) 469.4
Formula

C22H20F5N3O3

CAS No. 847925-91-1
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 94 mg/mL (200 mM)
Water <1 mg/mL (<1 mM)
Ethanol 16 mg/mL (34 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 15 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 Propanediamide, N1-[(7S)-6,7-dihydro-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2,2-dimethyl-N3-(2,2,3,3,3-pentafluoropropyl)-

Research Area

Customer Reviews (3)


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Rating
Source Dr. Barbara Bedogni of Case Western Reserve University. RO4929097 purchased from Selleck
Method Crystal violet staining
Cell Lines WM266-4, K457, SK-Mel2 human metastatic melanoma cells
Concentrations 10 μM
Incubation Time 4 d
Results Melanoma growth inhibition by the concomitant treatment with a TKI and the GSI inhibitor RO4929097. 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.

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Rating
Source Stem Cells. 2014 Jan;32(1):301-12 . RO4929097 purchased from Selleck
Method CellTiter-Blue assay
Cell Lines GICs
Concentrations 0.1-10 uM
Incubation Time 72 h
Results γ Secretase inhibitor RO4929097 effectively showed dose-dependent growth inhibition of GICs. panel of GICS lines was treated with various concentrations of γ secretase inhibitor RO4929097. Cells were treated with increasing concentrations of γ secretase inhibitor in triplicate wells for 72 hours, and cell viability was assessed by CellTiter-Blue assay as described in Materials and Methods. The results shown are of a single experiment with 3 independent replicates cell viability was measured by CellTiter-Blue assay. The graph depicts cell viability at 72 hours. Cell viability in the vehicle control was considered as to be 100%.

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Rating
Source Stem Cells. 2014 Jan;32(1):301-12 . RO4929097 purchased from Selleck
Method Western blot
Cell Lines GICs
Concentrations 0-5 uM
Incubation Time 0-72 h
Results γ Secretase inhibitor RO4929097 suppresses Notch signaling pathway in a dose- or time-dependent manner.

Product Citations (7)

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