Semagacestat (LY450139)

Information	Semagacestat (LY450139) is a γ-secretase blocker of Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively. Semagacestat also inhibits Notch signaling with IC50 of 14.1 nM.
Targets	Aβ42	Aβ40	Aβ38	Notch
IC50	10.9 nM	12.1 nM	12.0 nM	14.1 nM ^[1]
In vitro	Semagacestat reduces the secretion of Aβ42, Aβ40 and Aβ38 from H4 human glioma cells stably overexpressing human wild-type APP into the culture medium, with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively, without affecting cell viability. Semagacestat also increases β-CTF in cell lysates with EC_max of 16.0 nM, and the increase can be unexpectedly attenuated at high concentrations. Semagacestat inhibits Notch signaling with IC50 of 14.1 nM, and shows minimal Notch-sparing selectivity with Notch IC50/Aβ42 IC50 only 1.3. ^[1] Semagacestat causes a concentration-dependent decrease in Aβ40 secreted into the medium with IC50 of 111 nM from murine CTX expressing endogenous murine APP, but murine Aβ42 formation in CTX is roughly 12-fold less than Aβ40 in accordance with data for neurons from wild type mice. ^[2]
In vivo	Oral administration of Semagacestat (1 mg/kg) to 5.5-month old APP-transgenic Tg2576 mice significantly ameliorates memory deficits on spatial working memory using the Y-maze task, which disappears after 8 days subchronic dosing. LY450139 decreases hippocampal levels of both Aβ42 and Aβ40 at 10 mg/kg (22-23% reduction) and 30 mg/kg (36-41% reduction) and increases β-CTF at 0.3-10 mg/kg in a dose dependent manner with no inhibition on the processing of other γ-secretase substrates, such as Notch, N-cadherin or EphA4, in the brain, but impairs normal cognition in wild-type mice and 3-month-old Tg2576 mice failing to restore cognitive deficits in the Y-maze test. ^[1]
Clinical Trials	Phase III study has been completed in evaluating the effect of LY450139 on the progression of Alzheimer's disease as compared with placebo.
Features	Semagacestat is the best documented γ-secretase inhibitor that has reached clinical testing.

Information

Semagacestat (LY450139) is a γ-secretase blocker of Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively. Semagacestat also inhibits Notch signaling with IC50 of 14.1 nM.

Targets

Aβ42

Aβ40

Aβ38

Notch

IC50

10.9 nM

12.1 nM

12.0 nM

14.1 nM ^[1]

In vitro

Semagacestat reduces the secretion of Aβ42, Aβ40 and Aβ38 from H4 human glioma cells stably overexpressing human wild-type APP into the culture medium, with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, respectively, without affecting cell viability. Semagacestat also increases β-CTF in cell lysates with EC_max of 16.0 nM, and the increase can be unexpectedly attenuated at high concentrations. Semagacestat inhibits Notch signaling with IC50 of 14.1 nM, and shows minimal Notch-sparing selectivity with Notch IC50/Aβ42 IC50 only 1.3. ^[1] Semagacestat causes a concentration-dependent decrease in Aβ40 secreted into the medium with IC50 of 111 nM from murine CTX expressing endogenous murine APP, but murine Aβ42 formation in CTX is roughly 12-fold less than Aβ40 in accordance with data for neurons from wild type mice. ^[2]

In vivo

Oral administration of Semagacestat (1 mg/kg) to 5.5-month old APP-transgenic Tg2576 mice significantly ameliorates memory deficits on spatial working memory using the Y-maze task, which disappears after 8 days subchronic dosing. LY450139 decreases hippocampal levels of both Aβ42 and Aβ40 at 10 mg/kg (22-23% reduction) and 30 mg/kg (36-41% reduction) and increases β-CTF at 0.3-10 mg/kg in a dose dependent manner with no inhibition on the processing of other γ-secretase substrates, such as Notch, N-cadherin or EphA4, in the brain, but impairs normal cognition in wild-type mice and 3-month-old Tg2576 mice failing to restore cognitive deficits in the Y-maze test. ^[1]

Clinical Trials

Phase III study has been completed in evaluating the effect of LY450139 on the progression of Alzheimer's disease as compared with placebo.

Features

Semagacestat is the best documented γ-secretase inhibitor that has reached clinical testing.

Cellular APP processing assay and Notch signaling assay	H4 human glioma cells stably overexpressing human wild-type APP695 are treated with Semagacestat at various concentrations for 24 hours. Levels of Aβ42, Aβ40, and Aβ38 in the media are measured using separate ELISA kits. The expression vector of the constitutively active form of Notch (NotchΔE), encoding bases 1-60 and 5193-6657 of the human Notch1 coding region (NM_017617), is constructed into a pcDNA3.1 vector with a sequence modification from mouse to human. Notch signaling activity is evaluated using Cignal RBP-Jk Reporter Assay kit. RBP-Jk protein [CSL/CBF1/Su(H)/Lag1] is a transcription factor activated with Notch intracellular domain produced by γ-secretase. H4 cells are transiently transfected with the human NotchΔE expression vector and the RBP-Jk-responsive luciferase construct using Lipofectamine 2000, and then exposed to various concentrations of Semagacestat for 16 hours. Notch signaling is measured based on luciferase activity in the cell lysate using the Dual-Glo Luciferase Assay System.

Cell lines:	Murine cortical neurons and cerebellar granule cells
Concentrations:	Dissolved in DMSO, final concentration ~10 μM
Incubation Time:	24 hours
Method:	Cells are incubated with Semagacestat for 24 hours. For detection of cell viability, the percentage of viable cells is quantified by their capacity to reduce 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) following incubation with 0.5 mg/mL MTT for 60 minutes. For the detection of sAPP species, cells are lysed and analysed by western blotting.

Cell lines:

Murine cortical neurons and cerebellar granule cells

Concentrations:

Dissolved in DMSO, final concentration ~10 μM

Incubation Time:

24 hours

Method:

Cells are incubated with Semagacestat for 24 hours. For detection of cell viability, the percentage of viable cells is quantified by their capacity to reduce 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) following incubation with 0.5 mg/mL MTT for 60 minutes. For the detection of sAPP species, cells are lysed and analysed by western blotting.

Animal Models:	Female Tg2576 mice expressing human APP695 with the Swedish mutation (K670N/M671L)
Formulation:	Dissolved in 0.5% methyl cellulose.
Dosages:	~30 mg/kg
Administration:	Orally administered once daily

Animal Models:

Female Tg2576 mice expressing human APP695 with the Swedish mutation (K670N/M671L)

Formulation:

Dissolved in 0.5% methyl cellulose.

Dosages:

~30 mg/kg

Administration:

Orally administered once daily

Molecular Weight (WM):	361.44
Formula:	C₁₉H₂₇N₃O₄
CAS No.:	425386-60-3
Synonyms:	N/A

Molecular Weight (WM):

361.44

Formula:

C₁₉H₂₇N₃O₄

CAS No.:

425386-60-3

Synonyms:

N/A

Dissolve in (25°C):	DMSO ≥72mg/mL
	Water <1mg/mL
	Ethanol ≥43mg/mL
Storage:	2 years-20°CPowder
	1 week-4°Cin DMSO
	1 month-80°in DMSO

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Biological Activity

Protocol (Only for Reference)

Kinase Assay: ^[1]

Cell Assay: ^[2]

Animal Study:^[1]

References

Chemical Information

Quality Control & MSDS

Research Area

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