RO4929097 is a potent and selective γ-secretase inhibitor with IC50 value of 4nM for γ-secretase enzyme assay, as well as EC50 values of 14nM and 5nM for Aβ40 and Notch processing in engineered cell lines, respectively. As γ-secretase is the key component of the enzymatic complex cleaving and activating NOTCH, RO4929097 can also inhibit NOTCH signaling indirectly. Treatment with RO4929097 dose-dependently suppressed the production of intracellular Notch at concentration ranging in 0.1-5μM for 5 days, reduced the expression of the downstream Notch target Hes1 at concentration ranging in 0.1-1μM for 24h, and producd a less transformed morphology in A549 cells. Orally administration of RO4929097 at dose of 3, 10, 30 and 60mg/kg, qd, for 14 days achieved tumor growth inhibition by 66%, 77%, 79% and 88% in the A549 xenograft model. Treatment with 60 mg/kg RO4929097 twice daily with the 7+/14- schedule for a 21-day cycle achieved tumor growth inhibition by 91%. Inhibition of tumor growth remained prolonged and sustained up to 34 days post-treatment with reduced expression of several key angiogenic genes tested.
RO4929097 细胞实验
Cell Line
Concentration
Treated Time
Description
References
NCI-H358
5 μM
10 min
RO4929097 prevented Notch1 activation and partially rescued E-cadherin from the decrease during EDTA treatment
J Hematol Oncol. 2015 Feb 6;8:9.
NCI-H322M
5 μM
10 min
RO4929097 prevented Notch1 activation and partially rescued E-cadherin from the decrease during EDTA treatment
J Hematol Oncol. 2015 Feb 6;8:9.
T4302 CD133+ cells
100 nM
5 days
Assessed the impact of RO4929097 on T4302 CD133+ cells, showing that RO4929097 had only modest impact on cell viability.
Stem Cell Reports. 2017 Dec 12;9(6):1948-1960.
T4302 CD133- cells
100 nM
5 days
Assessed the impact of RO4929097 on T4302 CD133- cells, showing that these cells were essentially unresponsive to RO4929097.
Stem Cell Reports. 2017 Dec 12;9(6):1948-1960.
T4105 CD133+ cells
100 nM
3 days
Assessed the impact of RO4929097 on T4105 CD133+ cells, showing that RO4929097 significantly undermined tumor sphere formation.
Stem Cell Reports. 2017 Dec 12;9(6):1948-1960.
PANC-1 cells
10 μM
24 h
To detect the activity of TGF-β1-Smad2/3-Snail signaling, and it was found that RO4929097 significantly reversed the activation of TGF-β1-Smad2/3-Snail1 signaling by Numb-PRRL overexpression.
Cell Death Dis. 2022 Feb 23;13(2):173.
Miapaca-2 cells
10 μM
24 h
To detect the activity of TGF-β1-Smad2/3-Snail signaling, and it was found that RO4929097 significantly reversed the activation of TGF-β1-Smad2/3-Snail1 signaling by Numb-PRRL overexpression.
Cell Death Dis. 2022 Feb 23;13(2):173.
mouse primary chondrocytes
20 µM
RO4929097 inhibited Notch signaling and reduced the expression of senescence markers in chondrocytes
Nat Commun. 2023 Oct 4;14(1):6190.
Human fibroblast-like synoviocytes (FLS) from RA patients
5 μM
24 h
To investigate the effect of RO4929097 on Notch1 signaling in RA synoviocytes, results showed that RO4929097 reduced mRNA expression levels of Hey-1 and pro-inflammatory cytokines (TNF-α, IL-6, IL-12, IL-17), while increasing the expression of TGF-β and IL-10.
Theranostics. 2018 Sep 9;8(17):4795-4804.
Chronic lymphocytic leukemia (CLL) cells
0.5 µM
3 and 7 days
To evaluate the effect of RO4929097 on CLL cell viability. The results showed that RO4929097 had a minor effect on CLL cell viability after 3 days but significantly reduced CLL cell viability after 7 days.
Cells. 2020 Jun 18;9(6):1484.
RO4929097 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Pten knockout mice
Oral gavage
10 mg/kg
Once daily for 4 weeks
RO4929097 treatment significantly reduced tumor growth, decreased tumor malignancy and liver fibrosis, and induced a hepatic differentiation phenotype.
Hepatology. 2016 Mar;63(3):864-79
Nude mice
Subcutaneous GBM models
Oral
30 mg/kg
Daily for 14 days
Assessed the impact of RO4929097 combined with tipifarnib on subcutaneous GBM tumors, showing that the combination significantly reduced tumor growth.
Stem Cell Reports. 2017 Dec 12;9(6):1948-1960.
Mice
Posttraumatic OA model
Intraarticular injection
20 µM
Every two weeks, until 6 or 10 weeks post-surgery
RO4929097 alleviated cartilage degeneration and OA progression, reducing the number of senescent chondrocytes
Nat Commun. 2023 Oct 4;14(1):6190.
Mice
Collagen-induced arthritis (CIA) model
Intraperitoneal injection
1 mg/kg
Daily, until the end of the experiment
To investigate the effect of RO4929097 on arthritis progression in CIA model mice, results showed that RO4929097 significantly improved clinical outcomes, reduced synovial inflammation, cartilage erosion, and neutrophil infiltration, and increased Treg cell population.
Theranostics. 2018 Sep 9;8(17):4795-4804.
Mice
Intracranial glioma model
Oral
10 mg/kg
Daily
To evaluate the effect of RO4929097 in combination with oHSV therapy
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