RO4929097 is a potent and selective inhibitor of gamma-secretase, with IC50 of 4 nM and also inhibits Aβ40 and ICN with EC50 of 14 nM and 5 nM, producing inhibitory activity of Notch signaling in tumor cells. RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. 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 induced significant differences in event-free survival (EFS) distribution compared to control in 6 of 26 (23%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. 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.
|Source||Anticancer Drugs (2015). Figure 2. RO4929097|
|Cell Lines||NEM78 cells|
|Incubation Time||48 h|
|Results||RO4929097 reduces Notch effectors expression and cellular density and shows antiproliferative activity in NEM78 ependymoma cells.|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 90 mg/mL|
Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors.
Tolcher AW, et al. J Clin Oncol. 2012 Jul 1;30(19):2348-53. PMID: 22529266.
Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling.
Kolb EA, et al. Pediatr Blood Cancer. 2012 May;58(5):815-8. PMID: 22052798.
The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma.
Huynh C, et al. PLoS One. 2011;6(9):e25264. PMID: 21980408.
Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.
Luistro L, et al. Cancer Res. 2009 Oct 1;69(19):7672-80. PMID: 19773430.
|Related Gamma-secretase Products|
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LY3039478 is a novel and orally bioavailable inhibitor of Notch-1 intracellular domain (N1ICD) cleavage with IC50 of ~1 nM.
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