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Purity: =98.68%
RO4929097 (also called RO-4929097; RO04929097; R-4733) is a novel, potent and orally bioavailable small molecule inhibitor of γ-secretase (gamma secretase-GS) that may have antitumor properties. In a cell-free experiment, it suppresses γ-secretase with an IC50 of 4 nM. Additionally, it suppresses the cellular processing of Aβ40 and Notch, which are substrates for γ-secretase, with EC50s of 14 nM and 5 nM, respectively. By binding to GS, RO4929097 prevents Notch receptor activation, which may stop the growth of tumor cells. RO4929097 may be used to treat cancer because it has been shown that overexpression of the Notch signaling pathway is associated with an increase in the growth of tumor cells. Single-pass transmembrane proteins, like Notch receptors, are cleaved at residues within their transmembrane domains by the multi-subunit protease complex known as the integral membrane protein GS.
| Targets |
γ secretase (IC50 = 4 nM); Notch (IC50 = 5 nM); Aβ40 (IC50 = 14 nM)
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| ln Vitro |
RO4929097 inhibits the synthesis of ICN, which lowers the expression of Hes1, the downstream Notch target, and causes A549 cells to have a less altered morphology. In human tumor-derived cells, RO4929097 inhibits Notch processing[1]. Breast cancer cells are inhibited by RO4929097 (1 µM) to a 20% extent for SUM149 cells and 10% for SUM190 cells. The invasiveness of SUM149 cells is not significantly affected by RO4929097. Both cell lines experience a significant reduction in colony formation when exposed to RO4929097, with SUM149 cells showing the greatest effect[2]. In vitro, RO4929097 suppresses primary melanoma cell proliferation, anchorage independent growth, and sphere formation[3].
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| ln Vivo |
RO4929097 (3-60 mg/kg, p.o.) has a substantial inhibitory effect on tumor growth in nude mice with A549 NSCLC xenografts when compared to animals receiving vehicle treatment. Initially, treatment causes established A549 tumors to regress when mice are given 60 mg/kg RO4929097 twice daily according to the 7+/14-schedule[1]. Primary melanoma cell growth is inhibited in vivo by RO4929097. After mice were injected with 104 cells in vivo, it was found that the RO4929097-treated cells significantly delayed the formation of tumors compared to the vehicle-treated ones. The percentage of secondary tumors formed by RO4929097-treated cells is lower, and the secondary tumors formed by RO4929097-treated cells are smaller[3].
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| Enzyme Assay |
The Aβ peptides are quantified by ECL assays employing an Origen 1.5 Analyzer and a range of anti-Aβ antibodies following the use of RO4929097. The α-secretase cleavage site is immediately distal to an epitope in the Aβ peptide (within amino acids 18–21) that is bound by the 4G8 murine mAb. The C terminus, which is exposed following γ-secretase-mediated cleavage to produce amino acid 40 of the Aβ40 peptide, is bound by the G2–10 murine mAb. The C terminus of the Aβ42 peptide, which is generated by γ-secretase-mediated cleavage to produce amino acid 42, is bound by the rabbit antibody FCA3542. Biotin-LC-sulfo-N-hydroxysuccinimide-ester is used to biotinylate the 4G8 mAb. Using TAG-N-hydroxysuccinimide ester, the G2–10 and FCA3542 antibodies are ruthenylated. Biotinylated 4G8 and ruthenylated G2–10 are used to detect Aβ(x–40). Biotinylated 4G8 and ruthenylated FCA3542 are used to detect Aβ(x-42).
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| Cell Assay |
At a density of 5 × 104 cells, the IBC cell lines SUM149 and SUM190 are seeded. 0.1 nM to 10 μM of RO4929097 are administered as a vehicle or escalating doses the following day. Trypsinization of the cells is done after 72 hours, and a hemocytometer is used to count the viable cells..
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| Animal Protocol |
Mice: Mice treated with RO4929097 are given oral doses of suspensions ranging from 3 to 60 mg/kg RO4929097 in accordance with the prescribed regimens. RO4929097 is dosed at 60 mg/kg/d every other week for 4 weeks (7+/7- × 2 cycles) in the Calu-6 xenograft model. RO4929097 is dosed once daily at 10 mg/kg for 21 days for all other xenograft models. One-way ANOVA, the post hoc Bonferroni t test, and the Mann-Whitney rank-sum test are used to determine statistical analysis. When P ≤ 0.05, differences between groups are deemed significant. A549 tumors from both the vehicle-treated and specific RO4929097-treated groups are taken, processed, and embedded in paraffin for an overnight fix. They are then sectioned at 5 μM and stained with H&E for histopathology evaluation. The histology images were obtained with an Olympus BX51 microscope (×40 objective) mounted on a Nikon DS-Fi1 equipped with the NIS-Elements F2.20 software. Three A549 tumours are flash-frozen for Western blot analysis, one for each of the two groups (7 (60 mg/kg) or 21 days (3 and 30 mg/kg). H-200 antibody is used at a dilution of 1:1,000 to detect collagen type V, and at a dilution of 1:5,000 to detect MFAP5.
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| References |
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| Molecular Formula |
C22H20F5N3O3
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| Molecular Weight |
469.4
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| Exact Mass |
469.14
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| Elemental Analysis |
C, 56.29; H, 4.29; F, 20.24; N, 8.95; O, 10.23
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| CAS # |
847925-91-1
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| Appearance |
Solid powder
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| SMILES |
CC(C)(C(=O)NCC(C(F)(F)F)(F)F)C(=O)N[C@H]1C2=CC=CC=C2C3=CC=CC=C3NC1=O
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| InChi Key |
OJPLJFIFUQPSJR-INIZCTEOSA-N
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| InChi Code |
InChI=1S/C22H20F5N3O3/c1-20(2,18(32)28-11-21(23,24)22(25,26)27)19(33)30-16-14-9-4-3-7-12(14)13-8-5-6-10-15(13)29-17(16)31/h3-10,16H,11H2,1-2H3,(H,28,32)(H,29,31)(H,30,33)/t16-/m0/s1
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| Chemical Name |
2,2-dimethyl-N-[(7S)-6-oxo-5,7-dihydrobenzo[d][1]benzazepin-7-yl]-N'-(2,2,3,3,3-pentafluoropropyl)propanediamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.33 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 2% DMSO+30% PEG 300+5% Tween+ddH2O: 10 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1304 mL | 10.6519 mL | 21.3038 mL | |
| 5 mM | 0.4261 mL | 2.1304 mL | 4.2608 mL | |
| 10 mM | 0.2130 mL | 1.0652 mL | 2.1304 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01131234 | Completed | Drug: Cediranib Maleate Other: Pharmacological Study |
Adult Glioblastoma Adult Gliosarcoma |
National Cancer Institute (NCI) |
May 2010 | Phase 1 |
| NCT01141569 | Completed | Drug: Gamma-Secretase Inhibitor RO4929097 Other: Laboratory Biomarker Analysis |
Stage IV Renal Cell Cancer Recurrent Renal Cell Carcinoma |
National Cancer Institute (NCI) |
June 2010 | Phase 2 |
| NCT01198535 | Completed | Biological: Cetuximab Other: Pharmacological Study |
Stage IVA Colon Cancer Stage IVA Rectal Cancer |
National Cancer Institute (NCI) |
September 2010 | Phase 2 |
| NCT01154452 | Completed | Drug: Vismodegib Other: Pharmacological Study |
Chondrosarcoma Ovarian Sarcoma |
National Cancer Institute (NCI) |
June 2010 | Phase 1 Phase 2 |
| NCT01175343 | Completed | Other: Laboratory Biomarker Analysis Drug: Gamma-Secretase Inhibitor RO4929097 |
Recurrent Ovarian Carcinoma Stage IV Ovarian Cancer |
National Cancer Institute (NCI) |
July 2010 | Phase 2 |
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