MK-0752 is a potent gamma secretase inhibitor, an enzyme required for Notch pathway activation. MK-0752 reduces Aβ40 production with IC50 of 5 nM in human SH-SY5Y cells. MK-0752 blocks Notch-intracellular domain (ICD) cleavage and its subsequent nuclear translocation in vitro. MK-0752 treatment increases levels of Aβ 1-14, Aβ 1-15 and Aβ 1-16, while decreases levels of Aβ 1-17. Phase I clinical trials has been completed in 2006, and the results reported showed that MK-0752 was well-tolerated in a limited number of patients below 300 mg/m2, and further enrollment was underway to establish the MTD.
|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 80 mg/mL
Ethanol 40 mg/mL
|Source||Oncol Lett (2016). Figure 2. MK-0752|
|Method||Flow cytometric analysis|
|Incubation Time||48 h|
|Results||Furthermore, the second GSI MK.0752, which is currently under clinical evaluation for various cancer types, also significantly enhanced TRAIL.induced apoptosis in T.ALL cells|
Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors.
Krop I, et al. J Clin Oncol. 2012 Jul 1;30(19):2307-13. PMID: 22547604.
Phase I trial of MK-0752 in children with refractory CNS malignancies: a pediatric brain tumor consortium study.
Fouladi M, et al. J Clin Oncol. 2011 Sep 10;29(26):3529-34. PMID: 21825264.
Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor.
Harrison H, et al. Cancer Res. 2010 Jan 15;70(2):709-18. PMID: 20068161.
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