RO4929097 | CAS#847925-91-1 | gamma secretase inhibitor

MedKoo Cat#: 202412 | Name: RO4929097

Description:

WARNING: This product is for research use only, not for human or veterinary use.

RO4929097, also known as RO 04929097, is an orally bioavailable, small-molecule gamma secretase (GS) inhibitor with potential antitumor activity. RO4929097 Inhibits Subretinal Fibrosis Via Suppressing Notch and ERK1/2 Signaling in Laser-Induced Mouse Model. O4929097 attenuated LPS-induced osteolysis in mice. In conclusion, our findings indicate that Notch may represent a potential therapeutic target for the treatment of osteolytic diseases.

Chemical Structure

RO4929097

CAS#847925-91-1

Theoretical Analysis

MedKoo Cat#: 202412

Name: RO4929097

CAS#: 847925-91-1

Chemical Formula: C22H20F5N3O3

Exact Mass: 469.1425

Molecular Weight: 469.40

Elemental Analysis: C, 56.29; H, 4.29; F, 20.24; N, 8.95; O, 10.23

Price and Availability

Size	Price	Availability
25mg	USD 450.00	2 Weeks
50mg	USD 750.00	2 Weeks
100mg	USD 1,250.00	2 Weeks
200mg	USD 1,950.00	2 Weeks
500mg	USD 2,950.00	2 Weeks
1g	USD 4,650.00	2 Weeks
2g	USD 7,450.00	2 Weeks

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Related CAS #

No Data

Synonym

R4733; R 4733; R-4733; RO4929097; RO-4929097; RO 4929097; RO04929097; RO-04929097; RO 04929097.

IUPAC/Chemical Name

(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 Key

OJPLJFIFUQPSJR-INIZCTEOSA-N

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

SMILES Code

O=C(N[C@H]1C2=CC=CC=C2C3=CC=CC=C3NC1=O)C(C)(C)C(NCC(F)(F)C(F)(F)F)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, DMF, and ethanol

Shelf Life

>5 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

RO4929097 decreased the levels of NOTCH transcriptional target HES1. This was accompanied by reduced proliferation and impaired ability to form colonies in soft agar and to organize in tridimensional spheres. 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. Finally, increased gene expression of NOTCH signaling components correlated with shorter post recurrence survival in metastatic melanoma cases. Our data support NOTCH inhibition as a promising therapeutic strategy against melanoma. (source: PLoS One. 2011;6(9):e25264. Epub 2011 Sep 29) (last updated: 4/18/2016).

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Ro 4929097 is a potent inhibitor of γ-secretase (IC50 = 4 nM) that blocks both Aβ40 and Notch processing (IC50s = 14 and 5 nM, respectively). It displays >100-fold selectivity for γ-secretase over a panel of 75 other enzymes, receptors, and ion channels. Ro 4929097 does not block tumor cell growth or induce apoptosis; it produces a less transformed, flattened, slower-growing phenotype. Ro 4929097 is orally active against cancer xenograft models, altering gene expression related to angiogenesis and cell differentiation. Ro 4929097 also reduces tumor initiating potential of melanoma cells in vivo by blocking Notch-dependent gene expression.

In vitro activity:

The initiator caspases (caspases-8 and -9), effector caspase (caspase-3) and its downstream substrate PARP were induced after Resveratrol + RO 4929097 (RSV+GSI) exposure. This study establish the role of CDK4 in the regulation of autophagy/apoptosis transition induced by RSV and GSI in glioblastoma multiforme cells. This new synergistic therapeutic combination may have therapeutic value for glioblastoma multiformepatients. Reference: Am J Cancer Res. 2021 Dec 15;11(12):5933-5950. https://pubmed.ncbi.nlm.nih.gov/35018234/

In vivo activity:

RO 4929097exerts its antifibrotic effect by directly inhibiting Notch signaling and indirectly suppressing ERK1/2 signaling. Targeting Notch signaling might provide a therapeutic strategy in prevention and treatment of subretinal fibrosis in neovascular age-related macular degeneration. Reference: Invest Ophthalmol Vis Sci. 2022 Sep 1;63(10):14. https://pubmed.ncbi.nlm.nih.gov/36155746/

	Solvent	mg/mL	mM
Solubility
	DMF	25.0	53.25
	DMSO	15.0	31.96
	Ethanol	10.0	21.30

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 469.40 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Giordano F, Montalto FI, Panno ML, Andò S, De Amicis F. A Notch inhibitor plus Resveratrol induced blockade of autophagy drives glioblastoma cell death by promoting a switch to apoptosis. Am J Cancer Res. 2021 Dec 15;11(12):5933-5950. PMID: 35018234; PMCID: PMC8727809. 2. Yang J, Hu Y, Wang L, Sun X, Yu L, Guo W. Human umbilical vein endothelial cells derived-exosomes promote osteosarcoma cell stemness by activating Notch signaling pathway. Bioengineered. 2021 Dec;12(2):11007-11017. doi: 10.1080/21655979.2021.2005220. PMID: 34781817; PMCID: PMC8810022. 3. Zhang C, Qin S, Xie H, Qiu Q, Wang H, Zhang J, Luo D, Zhang J. RO4929097, a Selective γ-Secretase Inhibitor, Inhibits Subretinal Fibrosis Via Suppressing Notch and ERK1/2 Signaling in Laser-Induced Mouse Model. Invest Ophthalmol Vis Sci. 2022 Sep 1;63(10):14. doi: 10.1167/iovs.63.10.14. PMID: 36155746; PMCID: PMC9526367. 4. Gounder MM, Rosenbaum E, Wu N, Dickson MA, Sheikh TN, D'Angelo SP, Chi P, Keohan ML, Erinjeri JP, Antonescu CR, Agaram N, Hameed MR, Martindale M, Lefkowitz RA, Crago AM, Singer S, Tap WD, Takebe N, Qin LX, Schwartz GK. A Phase Ib/II Randomized Study of RO4929097, a Gamma-Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma. Clin Cancer Res. 2022 Apr 14;28(8):1586-1594. doi: 10.1158/1078-0432.CCR-21-3874. PMID: 35110418; PMCID: PMC9187109.

In vitro protocol:

In vivo protocol:

1. Zhang C, Qin S, Xie H, Qiu Q, Wang H, Zhang J, Luo D, Zhang J. RO4929097, a Selective γ-Secretase Inhibitor, Inhibits Subretinal Fibrosis Via Suppressing Notch and ERK1/2 Signaling in Laser-Induced Mouse Model. Invest Ophthalmol Vis Sci. 2022 Sep 1;63(10):14. doi: 10.1167/iovs.63.10.14. PMID: 36155746; PMCID: PMC9526367. 2. Gounder MM, Rosenbaum E, Wu N, Dickson MA, Sheikh TN, D'Angelo SP, Chi P, Keohan ML, Erinjeri JP, Antonescu CR, Agaram N, Hameed MR, Martindale M, Lefkowitz RA, Crago AM, Singer S, Tap WD, Takebe N, Qin LX, Schwartz GK. A Phase Ib/II Randomized Study of RO4929097, a Gamma-Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma. Clin Cancer Res. 2022 Apr 14;28(8):1586-1594. doi: 10.1158/1078-0432.CCR-21-3874. PMID: 35110418; PMCID: PMC9187109.

1: Zhang L, Shi L. The E2F1/MELTF axis fosters the progression of lung adenocarcinoma by regulating the Notch signaling pathway. Mutat Res. 2023 Jul- Dec;827:111837. doi: 10.1016/j.mrfmmm.2023.111837. Epub 2023 Sep 28. PMID: 37820570. 2: Giordano F, D'Amico M, Montalto FI, Malivindi R, Chimento A, Conforti FL, Pezzi V, Panno ML, Andò S, De Amicis F. Cdk4 Regulates Glioblastoma Cell Invasion and Stemness and Is Target of a Notch Inhibitor Plus Resveratrol Combined Treatment. Int J Mol Sci. 2023 Jun 13;24(12):10094. doi: 10.3390/ijms241210094. PMID: 37373242; PMCID: PMC10298906. 3: Ghosh S, Mitra P, Saha U, Nandi R, Jena S, Ghosh A, Roy SS, Acharya M, Biswas NK, Singh S. NOTCH pathway inactivation reprograms stem-like oral cancer cells to JAK-STAT dependent state and provides the opportunity of synthetic lethality. Transl Oncol. 2023 Jun;32:101669. doi: 10.1016/j.tranon.2023.101669. Epub 2023 Apr 11. PMID: 37054548; PMCID: PMC10122064. 4: Karthika CL, Venugopal V, Sreelakshmi BJ, Krithika S, Thomas JM, Abraham M, Kartha CC, Rajavelu A, Sumi S. Oscillatory shear stress modulates Notch-mediated endothelial mesenchymal plasticity in cerebral arteriovenous malformations. Cell Mol Biol Lett. 2023 Mar 18;28(1):22. doi: 10.1186/s11658-023-00436-x. PMID: 36934253; PMCID: PMC10024393. 5: Pathak Y, Camps I, Mishra A, Tripathi V. Targeting notch signaling pathway in breast cancer stem cells through drug repurposing approach. Mol Divers. 2023 Dec;27(6):2431-2440. doi: 10.1007/s11030-022-10561-y. Epub 2022 Nov 14. PMID: 36376717. 6: Zhang C, Qin S, Xie H, Qiu Q, Wang H, Zhang J, Luo D, Zhang J. RO4929097, a Selective γ-Secretase Inhibitor, Inhibits Subretinal Fibrosis Via Suppressing Notch and ERK1/2 Signaling in Laser-Induced Mouse Model. Invest Ophthalmol Vis Sci. 2022 Sep 1;63(10):14. doi: 10.1167/iovs.63.10.14. PMID: 36155746; PMCID: PMC9526367. 7: Lin L, Wu X, Jiang Y, Deng C, Luo X, Han J, Hu J, Cao X. Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma. PeerJ. 2022 May 24;10:e13402. doi: 10.7717/peerj.13402. PMID: 35646490; PMCID: PMC9138047. 8: Sheng W, Tang J, Cao R, Shi X, Ma Y, Dong M. Numb-PRRL promotes TGF-β1- and EGF-induced epithelial-to-mesenchymal transition in pancreatic cancer. Cell Death Dis. 2022 Feb 23;13(2):173. doi: 10.1038/s41419-022-04609-y. PMID: 35197444; PMCID: PMC8866481. 9: Gounder MM, Rosenbaum E, Wu N, Dickson MA, Sheikh TN, D'Angelo SP, Chi P, Keohan ML, Erinjeri JP, Antonescu CR, Agaram N, Hameed MR, Martindale M, Lefkowitz RA, Crago AM, Singer S, Tap WD, Takebe N, Qin LX, Schwartz GK. A Phase Ib/II Randomized Study of RO4929097, a Gamma-Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma. Clin Cancer Res. 2022 Apr 14;28(8):1586-1594. doi: 10.1158/1078-0432.CCR-21-3874. PMID: 35110418; PMCID: PMC9187109. 10: Giordano F, Montalto FI, Panno ML, Andò S, De Amicis F. A Notch inhibitor plus Resveratrol induced blockade of autophagy drives glioblastoma cell death by promoting a switch to apoptosis. Am J Cancer Res. 2021 Dec 15;11(12):5933-5950. PMID: 35018234; PMCID: PMC8727809. 11: Means-Powell JA, Mayer IA, Ismail-Khan R, Del Valle L, Tonetti D, Abramson VG, Sanders MS, Lush RM, Sorrentino C, Majumder S, Miele L. A Phase Ib Dose Escalation Trial of RO4929097 (a γ-secretase inhibitor) in Combination with Exemestane in Patients with ER + Metastatic Breast Cancer (MBC). Clin Breast Cancer. 2022 Feb;22(2):103-114. doi: 10.1016/j.clbc.2021.10.013. Epub 2021 Oct 28. PMID: 34903452; PMCID: PMC8821119. 12: Kumari M, Krishnamurthy PT, Pinduprolu SKSS, Sola P. DR-5 and DLL-4 mAb Functionalized SLNs of Gamma-Secretase Inhibitors- An Approach for TNBC Treatment. Adv Pharm Bull. 2021 Sep;11(4):618-623. doi: 10.34172/apb.2021.070. Epub 2020 Oct 19. PMID: 34888208; PMCID: PMC8642801. 13: Yang J, Hu Y, Wang L, Sun X, Yu L, Guo W. Human umbilical vein endothelial cells derived-exosomes promote osteosarcoma cell stemness by activating Notch signaling pathway. Bioengineered. 2021 Dec;12(2):11007-11017. doi: 10.1080/21655979.2021.2005220. PMID: 34781817; PMCID: PMC8810022. 14: Zhang H, Xing J, Zhao L. Lysine-specific demethylase 1 induced epithelial- mesenchymal transition and promoted renal fibrosis through Jagged-1/Notch signaling pathway. Hum Exp Toxicol. 2021 Dec;40(12_suppl):S203-S214. doi: 10.1177/09603271211038743. Epub 2021 Aug 16. PMID: 34396798. 15: Chang SF, Yang WH, Cheng CY, Luo SJ, Wang TC. γ-secretase inhibitors, DAPT and RO4929097, promote the migration of Human Glioma Cells via Smad5-downregulated E-cadherin Expression. Int J Med Sci. 2021 Apr 26;18(12):2551-2560. doi: 10.7150/ijms.50484. PMID: 34104086; PMCID: PMC8176174. 16: Huang T, Zhao C, Zhao Y, Zhou Y, Wang L, Hang D. RO4929097 regulates RANKL- induced osteoclast formation and LPS-mediated bone resorption. Aging (Albany NY). 2021 May 2;13(9):12526-12536. doi: 10.18632/aging.202926. Epub 2021 May 2. PMID: 33934091; PMCID: PMC8148457. 17: Rahman A, Lozada-Martinez ID, Rahman S, Ataullah AHM, Muñoz-Baez K, Moscote- Salazar LR, Agrawal A, Rahman MM. Letter: A Phase II and Pharmacodynamic Trial of RO4929097 for Patients With Recurrent/Progressive Glioblastoma. Neurosurgery. 2021 Jun 15;89(1):E78-E79. doi: 10.1093/neuros/nyab097. PMID: 33822209. 18: Du Z, Li L, Sun W, Zhu P, Cheng S, Yang X, Luo C, Yu X, Wu X. Systematic Evaluation for the Influences of the SOX17/Notch Receptor Family Members on Reversing Enzalutamide Resistance in Castration-Resistant Prostate Cancer Cells. Front Oncol. 2021 Mar 10;11:607291. doi: 10.3389/fonc.2021.607291. PMID: 33791203; PMCID: PMC8006330. 19: Thippu Jayaprakash K, Hussein M, Shaffer R, Michael A, Nisbet A, Ajaz M. In Vitro Evaluation of Notch Inhibition to Enhance Efficacy of Radiation Therapy in Melanoma. Adv Radiat Oncol. 2020 Nov 25;6(2):100622. doi: 10.1016/j.adro.2020.11.007. PMID: 33732959; PMCID: PMC7940786. 20: Wang D, Lu J, Xu X, Yuan Y, Zhang Y, Xu J, Chen H, Liu J, Shen Y, Zhang H. Satellite Glial Cells Give Rise to Nociceptive Sensory Neurons. Stem Cell Rev Rep. 2021 Jun;17(3):999-1013. doi: 10.1007/s12015-020-10102-w. Epub 2021 Jan 3. PMID: 33389681.