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847925-91-1 (RO4929097)

1

Identification

RO4929097 RO4929097
Name RO4929097
Formula C22H20F5N3O3
MW 469.4
CAS No. 847925-91-1
EINECS
Smiles O=C(C(C)(C(NCC(F)(C(F)(F)F)F)=O)C)N[[email protected]]1C2=CC=CC=C2C3=CC=CC=C3NC1=O
Synonyms RO-4929097; RO 4929097; (S)-2,2-dimethyl-N1-(6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N3-(2,2,3,3,3-pentafluoropropyl)malonamide
InChI 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
2

Introduction

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. IC50 value: 4 nM Target: γ secretase in vitro: RO4929097 decreases the amount of Aβ peptides secreted into the culture medium in HEK293 cells with EC50 of 14 nM.

Background Information

RO4929097 is a potent and selective inhibitor of gamma-secretase, with IC50 of 4 nM and also inhibits Aβ40 and ICN with EC50 of 14 nM and 5 nM, producing inhibitory activity of Notch signaling in tumor cells. RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 induced significant differences in event-free survival (EFS) distribution compared to control in 6 of 26 (23%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. Moreover, RO4929097 affected the growth of human primary melanoma xenograft in NOD/SCID/IL2gammaR-/- mice and inhibited subsequent tumor formation in a serial xenotransplantation model, suggesting that inhibition of NOTCH signaling suppresses the tumor initiating potential of melanoma cells. In addition, RO4929097 decreased tumor volume and blocked the invasive growth pattern of metastatic melanoma cell lines in vivo. ......by AbMole BioScience
RO4929097 is an orally bioavailable, small-molecule gamma secretase (GS) inhibitor with an IC50 of 4 nM. ......by AdooQ BioScience, LLC
Description ......by Apexbio Technology LLC
RO4929097, a small-molecule inhibitor of γ secretase (IC50= 4 nM, EC50= 5 nM), inhibits cellular processing of Aβ40 (EC50= 14 nM) and Notch(EC50= 5 nM). In vitro: Decreases the amount of Aβ peptides secreted into the culture medium in HEK293 cells (EC50= ......by BOC Sciences
RO4929097 is a small molecule γ-secretase inhibitor (IC₅₀ = 4 nM). It binds to γ-secretase and blocks the activation of Notch receptors, which may inhibit tumor cell proliferation. RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. RO4929097 produces a less transformed and flattened slower-growing phenotype but does not induce apoptosis or block tumor cell proliferation. ......by BioVision, Inc.,
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. ......by MedChemexpress Co., Ltd.
RO4929097, also known as RO04929097, is an orally bioavailable, small-molecule gamma secretase (GS) inhibitor with potential antitumor activity. Gamma secretase inhibitor RO4929097 binds to GS and blocks activation of Notch receptors, which may inhibit tumor cell proliferation. The integral membrane protein GS is a multi-subunit protease complex that cleaves single-pass transmembrane proteins, such as Notch receptors, at residues within their transmembrane domains. Overexpression of the Notch signaling pathway has been correlated with increased tumor cell growth. ......by MedKoo Biosciences, Inc.
RO4929097 (RG 4733) is a potent, selective, orally active γ-secretase inhibitor with IC50 of 4 nM, inhibits Notch processing in the Notch cell-based reporter assay with IC50 of 5 nM; displays >100-fold selectivity against a panel of 75 other proteins of various types including receptors, ion channels and enzymes; inhibits Notch processing in human tumor-derived cells, inhibits the production of ICN, reducing the expression of the downstream Notch target Hes1 in A549 cells; demonstrates in vivo efficacy in A549 xenograft model.Lung CancerPhase 2 Discontinued ......by ProbeChem
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. ......by Selleck Chemicals LLC
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. ......by Target Molecule Corp.
3

Protocol(Only for Reference)

Cell Experiment

Cell lines SUM190 and SUM149 cells
Conditions 1 μM, 14 days for 2D cultures 7 days for 3D cultures
Method After treating with increasing doses of ionizing radiation in the presence or absence of the drug, 2D colonies were allowed to grow for 10–14 days, while the mammospheres were permitted to grow for 1 week. At 1 μM, RO4929097 was able to sensitize adherent cells to radiation with a more significant effect seen in SUM190 than in SUM149 cells. However, the same dose of inhibitor radioprotected cells grown under conditions that favor the enrichment of the cancer stem cells at higher doses of ionizing radiation. This discrepancy between 2D and 3D cultures suggested that cell contact may be needed for a Notch inhibitor to have a significant effect.
Source Apexbio Technology LLC
Cell lines WM35 and WM98.1 cell lines
Conditions 10 μM; 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.
Source Selleck Chemicals LLC

Animal Experiment

Animal Models NOD/SCID/IL2gammaR-/- (NOG) mice injected with WM3248 cells
Dosage Form Oral administration, 10 mg/Kg/day for 30 days
Applications There was a decrease in tumor growth with RO4929097 treatment, which was more appreciable after tumors were extracted for weight assessment. RO4929097-treated tumors also displayed lower expression of putative melanoma stem cell markers CD166, CD271 and JARID1B compared to vehicle-treated ones.
Source Apexbio Technology LLC
Animal Models Female nude mice bearing Calu-6 cells
Dosage 3 to 60 mg/kg
Formulation 1.0% Klucel in water with 0.2% Tween 80
Administration Oral administration
Source Selleck Chemicals LLC
4

Physical and Chemical Properties

Appearance:White to off-white Solid EBNumber:EB000028686

Storage condition

Store at -20°C by Apexbio Technology LLC

Solubility

Soluble in DMSO > 10 mM by Apexbio Technology LLC
DMSO ≥90mg/mL Water <1.2mg/mL Ethanol ≥14mg/mL by MedChemexpress Co., Ltd.
(25°C) * In vitro DMSO 94 mg/mL (200.25 mM); Ethanol16 mg/mL (34.08 mM); Water<1 mg/mL (<1 mM); In vivo 2% DMSO+30% PEG 300+5% Tween+ddH2O10mg/mL by Selleck Chemicals LLC
5

Mechanism and Indication

6

Clinical Information

Product Name Sponsor & Collaborators Indications Start Date End Date Phase
RO4929097 National Cancer Institute Metastatic colorectal cancer 2010/12/31 Phase 2 Clinical
RO4929097 National Cancer Institute Multiple myeloma 2010/12/31 2012/7/31 Phase 2 Clinical
RO4929097 University of Colorado at Denver and Health Sciences Center Pancreas tumor 2010/10/31 Phase 2 Clinical
RO4929097 National Cancer Institute Stage III melanoma 2010/9/30 Phase 2 Clinical
RO4929097 National Cancer Institute Stage IV melanoma 2010/9/30 Phase 2 Clinical
RO4929097 National Cancer Institute; The Cancer Institute of New Jersey Prostate tumor 2010/8/31 2012/8/31 Phase 2 Clinical
RO4929097 - Discontinued
RO4929097 - Phase 2
7

Safety Data of RO4929097

8

Spectral Information

9

Suppliers List

Company Price and Availability Country/Region
AbMole BioScience USA
AdooQ BioScience, LLC USA
Apexbio Technology LLC USA
Ark Pharm, Inc. USA
BLD Pharmatech
BOC Sciences
BioVision, Inc., USA
Biochempartner Co., Ltd China
CHEMSCENE, LLC 5mg/USD132();10mg/USD240() USA
Cayman Chemical Company USA
MedChemexpress Co., Ltd. 5mg/USD132();10mg/USD240() USA
MedKoo Biosciences, Inc. USA
ProbeChem
Selleck Chemicals LLC 5mg/USD170(In stock);10mM/1mLIn DMSO/USD238(In stock);10mg/USD320(In stock);50mg/USD970(In stock);200mg/USD2470(In stock) USA
Shanghai Haoyuan Chemexpress Co., Ltd. 5mg/USD132();10mg/USD240() China
Target Molecule Corp. 2mg/USD78();5mg/USD123();10mg/USD174();25mg/USD268();50mg/USD458() USA
10

Related Products

Other Forms of 847925-91-1

Name CAS No Formula MW

Recommended Compounds in γ-secretase Notch

Name CAS No Formula MW
LY-411575 (isomer 1) 209984-58-7 C26H23F2N3O4 479.48
YO-01027 209984-56-5 C26H23F2N3O3 463.48
gamma-secretase modulator 3 1431697-84-5 C24H23FN4OS 434.53
BMS 433796 935525-13-6 C19H16F2N4O4 402.35
BMS 299897 290315-45-6 C24H21ClF3NO4S 511.94
ELN 318463 851600-86-7 C19H20BrClN2O3S 471.8
MRK 003 623165-93-5 C25H31F6N3O2S 551.59
PF-3084014 1290543-63-3 C27H41F2N5O 489.64
CHF5074 749269-83-8 C16H11Cl2FO2 325.1617
Begacestat 769169-27-9 C9H8ClF6NO3S2 391.74
gamma-secretase modulator 1 1172637-87-4 C24H24N4OS 416.54
gamma-secretase modulator 2 1093978-89-2 C25H22F4N6O2 514.47
LY-411575 209984-57-6 C26H23F2N3O4 479.48
E 2012 870843-42-8 C25H26FN3O2 419.49
Semagacestat 425386-60-3 C19H27N3O4 361.44
DAPT 208255-80-5 C23H26F2N2O4 432.46
MK-0752 471905-41-6 C21H21ClF2O4S 442.9
BMS-708163 1146699-66-2 C20H17ClF4N4O4S 520.89
L-685458 292632-98-5 C39H52N4O6 672.85
Z-Ile-Leu-aldehyde 161710-10-7 C20H30N2O4 362.46

Recommended Compounds in Same Indication

Name CAS No Formula MW
Regorafenib 755037-03-7 C21H15ClF4N4O3 482.82
Regorafenib (Hydrochloride) 835621-07-3 C21H16Cl2F4N4O3 519.28
Trametinib 871700-17-3 C26H23FIN5O4 615.39
Quisinostat 875320-29-9 C21H26N6O2 394.4702
AT9283 896466-04-9 C19H23N7O2 381.43
Bicalutamide 90357-06-5 C18H14F4N2O4S 430.37
Tivantinib 905854-02-6 C23H19N3O2 369.42
IDO5L 914471-09-3 C9H7ClFN5O2 271.6356
MLN9708 1239908-20-3 C20H23BCl2N2O9 517.12
Panobinostat 404950-80-7 C21H23N3O2 349.43
Dovitinib 405169-16-6 C21H21FN6O 392.43
SB-590885 405554-55-4 C27H27N5O2 453.54
Sunitinib 557795-19-4 C22H27FN4O2 398.47
Brivanib (alaninate) 649735-63-7 C22H24FN5O4 441.46
Carfilzomib 868540-17-4 C40H57N5O7 719.91
Fenretinide 65646-68-6 C26H33NO2 391.55
Leuprolide (Acetate) 74381-53-6 C61H88N16O14 1269.45
LY2603618 911222-45-2 C18H22BrN5O3 436.3
ARRY-520 (R enantiomer) 885060-08-2 C20H22F2N4O2S 420.48
ARRY-520 885060-09-3 C20H22F2N4O2S 420.48
11

Route of Synthesis

12

References

[1]. Luistro L, et al. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res. 2009, 69(19), 7672-7680.

[2]. Debeb BG, et al. Pre-clinical studies of Notch signaling inhibitor RO4929097 in inflammatory breast cancer cells. Breast Cancer Res Treat. 2012.

[3]. Huynh C, et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PLoS One. 2011, 6(9), e25264.

Protocol Reference

[1] Debeb B G, Cohen E N, Boley K, et al. Pre-clinical studies of Notch signaling inhibitor RO4929097 in inflammatory breast cancer cells. Breast cancer research and treatment, 2012, 134(2): 495-510.

[2] Huynh C, Poliseno L, Segura M F, et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PloS one, 2011, 6(9): e25264.

......by Apexbio Technology LLC
13

More Information

RO4929097

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