YO-01027 is a dipeptidic gamma-secretase inhibitor with IC50 of 2.6 and 2.9 nM for the proteolysis of APPL and Notch, respectively. YO-01027 is used as an anti-Alzheimer agent. YO-01027 directly interact with the gamma-secretase complex. Unlike other gamma-secretase inhibitors,YO-01027 targets different functional domain of the complex. YO-01027 targets the N-terminal Presenilin fragment as well as another gamma-secretase inhibitor Compound E (Cpn E), whereas DFK167 and DAPT, another two gamma-secretase inhibitors, bind to the catalytic site of the Presenilin aspartyl protease subunit and the C-terminal Presenilin fragment, respectively. In a study, YO-01027 and CpnE indicated no apparent discrimination in blocking APPL and Notch cleavages, displaying statistically equivalent IC50 values for both substrates.
|Preparation method||Resuspending cells at ≤1 × 106 in 100 μL sorting buffer (PBS containing 0.5% bovine serum albumin, 2 mM EDTA) and incubating with preconjugated primary antibodies BEREP4-FITC (1:10), CD44-APC (1:20), and CD24-PE (1:10) for 10 minutes at 4 °C. Washing the cells in PBS and centrifuged at 800 × g for 2 minutes. For analysis, cells are resuspending in 500 μL of sorting buffer and using FACSCalibur to measure fluorescence and using WinMIDI 2.8 to analyze . For sorting, cells are resuspended in 1× HBSS after incubation with the primary antibodies. Cells are sorted, with HBSS as sheath fluid, at 16 p.s.i. using FACSAria. The CD24low cell population gated by FACS is the lowest quintile of CD24-positive cells plus all the CD24-negative cells.|
|Incubation time||3 days|
|Animal models||C57BL/6 mice|
|Formulation||0, 3Injected daily intraperitoneally, 10, 30 μmol/kg|
|Dosages||YO-01027 is suspended finely in 0.5% (w/v) hydroxypropylmethylcellulose (Methocel E4M) and 0.1% (w/v) Tween 80 in water.|
|Administration||Injected daily intraperitoneally|
|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|
|Related Gamma-secretase Products|
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LY900009 is a potent Notch inhibitor with IC50 of 0.27 nM.
LY3039478 is a novel and orally bioavailable inhibitor of Notch-1 intracellular domain (N1ICD) cleavage with IC50 of ~1 nM.
FLI-06 is a novel inhibitor of Notch signaling with EC50 of 2.3 μM.
Semagacestat (LY450139) is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively.
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