TNFAIP6 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
PMEPA1 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
Analysis of 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
SPOCK1 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
SERPINE1 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
F2RL1 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
Analysis of 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'H460a' at '6 hour'
COL5A1 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
(Factor value) COMPOUND/gamma secretase inhibitor RO4929097
HES1 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
EGFR DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '6 hour'
DNAJB9 UP in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'H460a' at '6 hour'
TM4SF20 UP in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
IL11 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
LEPREL1 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '6 hour'
COL1A1 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
RBP4 UP in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
HES1 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '6 hour'
KCNJ6 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
BPIFA1 UP in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'
Analysis of 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '6 hour'
Genes responses in A549 and H460 cells after GSI (RO4929097-001-003 , 2 uM) treatment. Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of gamma-secretase, producing inhibitory activity of Notch signaling in tumor cells. 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 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way. A549 and H460 cells were treated in quadruplicate with either vehicle or GSI (RP4929097-001-003, 2 uM) for 6 or 24 hours.
C3orf80 DOWN in 'gamma secretase inhibitor RO4929097' vs 'vehicle' in 'A549' at '24 hour'