Semagacestat (LY450139) is a γ-secretase blocker with an IC50 of 15 nM. Semagacestat also inhibits Notch signaling with IC50 of 14.1 nM. Semagacestat blocks the enzyme γ-secretase, which (along with β-secretase) is responsible for APP proteolysis.
Cytotechnology. 2019 Oct;71(5):881-891.
TGF-β1 signaling activates hepatic stellate cells through Notch pathway.
Semagacestat purchased from AbMole
Sci Adv. 2017 Feb 24;3(2):e1601068.
Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer’s disease
Semagacestat purchased from AbMole
. semagacesta, figure 6..jpg) |
Source | Science Advance (2017). semagacesta, Figure 6. (AbMole Bioscience) |
| Method | ||
| Cell Lines | ||
| Concentrations | 10mg/kg | |
| Incubation Time | ||
| Results | We showed that semagacestat was able to rescue levels of both NaV1.1 andNaV1.6, while LY2811376 only rescued those of NaV1.6 (one-way ANOVA for NaV1.1: F3,23 = 6.52, P = 0.0024; one-way ANOVA for NaV1.6: F3,23 = 5.911, P = 0.0038; Fig. 6). Therefore, beneficial effects of b- and g-secretase inhibitor treatments on the spatial object location task might be mediated, in part, by a rescue of the NaV levels, thereby restoring “normal” PV interneuron function |
. semagacesta, figure 5..jpg) |
Source | Science Advance (2017). semagacesta, Figure 5. (AbMole Bioscience) |
| Method | ||
| Cell Lines | ||
| Concentrations | 10mg/kg | |
| Incubation Time | ||
| Results | In addition, we also confirmed that hippocampal b-CTF contents were decreased following the LY2811376 treatment but increased after the semagacestat treatment (one-sample t test against TgCRND8-vehicle: TgCRND8-LY2811376: t4 = 14.42, P = 0.0001; TgCRND8-semagacestat: t8 = 14.30, P < 0.0001). Given the distinct effect of LY2811376 and semagacestat treatments on both APP metabolite levels and cognitive performances, it is likely that different APP metabolites are responsible for the deficits of TgCRND8 mice in the spatial object location task and in the objectplace association task. |
| Molecular Weight | 361.44 |
| Formula | C19H27N3O4 |
| CAS Number | 425386-60-3 |
| Solubility (25°C) | DMSO 62 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
[2] Shinji Tagami, et al. Semagacestat Is a Pseudo-Inhibitor of γ-Secretase
[3] Rachelle S Doody, et al. A phase 3 trial of semagacestat for treatment of Alzheimer's disease
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β-Secretase inhibitor ([Asn670, Sta671, Val672]-Amyloid β Peptide (662-675)) is a β-secretase and BACE1 inhibitor (IC50: 25 nM for β-secretase). |
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Mca-SEVNLDAEFK(Dnp) is a Beta-secretase 1 (BACE-1) peptide FRET substrate, containing the 'Swedish' Lys-Met/Asn-Leu mutation of the amyloid precursor protein (APP) β-secretase cleavage site. |
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