RO4929097

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 Cancer Phase 2 Discontinued (In Vitro) :RO4929097 inhibits the production of ICN reducing the expression of the downstream Notch target, Hes1, producing a less transformed morphology in A549 cells. RO4929097 inhibits Notch processing in human tumor-derived cells. RO4929097 (1 μM) inhibits the growth of breast cancer cells, and the inhibition is 20% for SUM149 and 10% for SUM190 cells. RO4929097 does not have a marked effect in invasiveness of SUM149 cells. RO4929097 significantly reduces colony formation by both cell lines with the effect being more notable in SUM149 than by SUM190 cells. RO4929097 inhibits proliferation, anchorage independent growth, and sphere formation of primary melanoma cells in vitro. (In Vivo) :RO4929097 (3-60 mg/kg, p.o.) results in significant tumor growth inhibition in nude mice bearing A549 NSCLC xenografts, compared with vehicle-treated animals. When mice are treated with 60 mg/kg RO4929097 twice daily with the 7+/14- schedule, treatment initially causes regression of established A549 tumors. RO4929097 impairs the growth of primary melanoma cells in vivo. The percentage of secondary tumors formed by RO4929097-treated cells is lower; the secondary tumors formed by RO4929097-treated cells are smaller; a significant delay in tumor formation by the RO4929097-treated cells compared to the vehicle-treated ones is observed in mice injected with 104 cells in vivo.