RO4929097 847925-91-1

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Molecular Weight:

469.4 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.






Biological Activity


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. 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. 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.


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. 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. For IL6 and IL8 overexpressing
tumors, RO4929097 no longer impacts angiogenesis or the infiltration of
tumor associated fibroblasts.

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Product Categories : Proteases > Gamma-secretase Inhibitor