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Fig. 1 · Structure
Cat. No.
A11393
CAS No.
870843-42-8
Formula
C25H26FN3O2
Mol. Weight
419.49

Documents & Downloads

E 2012

Cat. No. A11393 CAS 870843-42-8

gamma-secretase modulator

E 2012 is γ-secretase inhibitor.

In Stock

Publications for E 2012

1 publication citing this product

  1. Yesuvadian R, .et al. , Biochem Biophys Res Commun., 2014, May 16;447(4):590-5 PMID: 24747079
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Biological Activity

Bioactivity / Mechanism

E2012 modulates γ-secretase-dependent APP processing. In presenilin-reconstituted cells it shifted secreted Aβ toward shorter species. Parent E2012 also competed with an E2012-derived photoaffinity probe for PS1 N-terminal-fragment labeling, supporting a presenilin interaction; the probe is a distinct molecule. [1]

Literature-reported observations and conditions; not Adooq-tested protocols or general treatment recommendations.

In Vitro Studies

In DKONL cells expressing Swedish-mutant APP and wild-type PS1, E2012 reduced Aβ40/42 and increased Aβ37/38 without a reported change in total secreted Aβ or APP C-terminal fragments. The tested range was 0.01–10 μM; these concentrations are treatment conditions, not IC50 values. [1]

In a separate HEK293 panel, 1 μM E2012 for 48 h did not detectably modulate secreted peptide profiles from truncated EphA4, EphB2 or E-cadherin constructs. These negative findings apply to the tested profiles; E-cadherin processing was γ-secretase-independent in this model. [2]

Cellular redistribution of secreted Aβ peptides

Cell-based study · DKONL mouse embryonic fibroblasts lacking endogenous presenilin 1/2, expressing Swedish-mutant APP and wild-type PS1 [1]

E2012 lowered secreted Aβ40 and Aβ42 while increasing shorter Aβ37/38. Total secreted Aβ and APP C-terminal fragment abundance were not detectably affected in the reported immunoblots.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Aβ42/(Aβ38 + Aβ40 + Aβ42), percentage; mean ± SEM, n = 4Aβ42 ratio (%) 0, 0.01, 0.1, 1 and 10 μM E2012: 5.9 ± 0.39, 6.1 ± 0.32, 3.4 ± 0.25, 2.4 ± 0.82 and 2.7 ± 0.12%, respectively[1]
Secreted Aβ profile, total Aβ and cellular APP CTFQualitative immunoblot response Aβ37/38 increased and Aβ40/42 decreased; no reported effect on total secreted Aβ or APP CTF[1]

Literature-Reported Treatment Conditions

Treatment concentration
0, 0.01, 0.1, 1 and 10 μM
Method
Cell treatment; conditioned-medium ELISA/immunoblot and cell-lysate immunoblot
Reported limits
Treatment duration and vehicle for Figure 1B were not specified in the read methods/caption; do not import them from later assays.
Methods and source locations

Compound reported in the paper: E2012; Compound label in the paper: E2012 (parent compound)

Applies to the E2012 material reported in this paper; does not validate an Adooq lot or establish salt equivalence.

Figure 1A,B; Results: Pharmacological activity of E2012 and its photoaffinity probe; Materials and Methods

Aβ42/(Aβ38 + Aβ40 + Aβ42), percentage; mean ± SEM, n = 4: Specific sandwich ELISAs; denominator is the three specified species, not all Aβ species. — Figure 1B, printed Aβ42-ratio values and caption

Secreted Aβ profile, total Aβ and cellular APP CTF: Urea/standard SDS-PAGE immunoblots; no exact band-intensity estimates extracted. — Figure 1B, immunoblots and accompanying Results

Competition of a photoaffinity probe at PS1 NTF

Biochemical assay · CHAPSO-solubilized membrane fraction from DKONL cells expressing wild-type PS1 [1]

The E2012-derived probe ER-000390411 labeled PS1 NTF. Parent E2012 reduced this labeling in a concentration-dependent manner, supporting an E2012 interaction with the PS1 N-terminal region.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Probe labeling of PS1 NTF in the presence of parent E2012Qualitative competition Labeling with 0.2 μM ER-000390411 was reduced by 20 μM E2012; Figure 1E shows competition with 0, 2, 10 and 20 μM E2012[1]

Literature-Reported Treatment Conditions

Treatment concentration
Parent E2012: 20 μM in Figure 1D; 0, 2, 10 and 20 μM in Figure 1E
Exposure duration
Competition incubation overnight; probe incubation 5 min before labeling, as described in shared PAL methods
Method
Membrane photoaffinity competition assay
Co-treatment
0.2 μM ER-000390411 analytical probe; ST1120 is a separate competitor comparator
Reported limits
Vehicle and replicate count for Figure 1D,E were not specified in the read methods/caption.
Methods and source locations

Compound reported in the paper: E2012; Compound label in the paper: E2012 (parent compound)

Applies to the E2012 material reported in this paper; does not validate an Adooq lot or establish salt equivalence.

Figure 1A,D,E; Results: ER-000390411 binds to the region from Q61 to D110 (opening paragraph); Photoaffinity labeling methods

Probe labeling of PS1 NTF in the presence of parent E2012: Photoaffinity labeling, streptavidin enrichment and immunoblotting. Probe-free and input controls plus other complex components and APP CTF were examined. — Figure 1D,E and Photoaffinity labeling methods

E2012 response of non-APP substrate peptide profiles

Cell-based study · HEK293 cells stably expressing FLAG-tagged ectodomain-truncated E-cadherin, EphB2 or EphA4 [2]

At 1 μM for 48 h, E2012 did not show detectable modulation of the secreted peptide profiles from the three tested constructs. These are model- and endpoint-specific negative findings.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Secreted E-cadherin-, EphB2- and EphA4-derived peptide profilesQualitative peptide-profile comparison No modulation reported for E2012 at 1 μM; Figure 5 caption: N = 4–5 experiments in duplicates (n = 2), error bars SEM[2]

Literature-Reported Treatment Conditions

Treatment concentration
1 μM
Exposure duration
48 h
Method
Cell exposure followed by conditioned-medium immunoprecipitation/MALDI-TOF MS
Vehicle
DMSO control; percentage not specified for this panel
Reported limits
Methods 2.5 describes triplicates/repeats, whereas Figure 5 caption specifies N = 4–5 in duplicates. Caption-specific replication is retained; the reporting difference remains unresolved.
Methods and source locations

Compound reported in the paper: E2012; Compound label in the paper: E2012 (parent compound)

Applies to the E2012 material reported in this paper; does not validate an Adooq lot or establish salt equivalence.

Figure 5A–C; Results 3.2–3.3; Methods 2.1, 2.3, 2.5, 2.8

Secreted E-cadherin-, EphB2- and EphA4-derived peptide profiles: Anti-FLAG immunoprecipitation and MALDI-TOF MS; DMSO control and L685,458 inhibitor comparator. No exact bar percentages inferred. — Figure 5A–C; Results 3.3

In Vivo Studies

In seven male beagles, a randomized cross-over study of single oral E2012 doses (20 and 80 mg/kg) detected transient changes in relative CSF APLP1 peptide signals. At 80 mg/kg, APLP1β25 decreased and β28 increased at selected times; β21/β22 and β27 findings were not significant. The assay measured relative peptide signals and did not test clinical benefit. [3]

Acute modulation of dog CSF APLP1 peptide signals

Animal study · Seven male beagle dogs (6–8 years); randomized cross-over [3]

Single oral E2012 shifted selected relative CSF APLP1 peptide signals, most clearly at 80 mg/kg. Several endpoints did not reach significance; responses tended to revert toward baseline over the sampling period.

Measured endpoints — not treatment concentrations
EndpointReported resultReference
Relative CSF APLP1β25 signal after 80 mg/kgWithin-dose longitudinal comparison Decreased at 4 h and 8 h versus predose (p = 0.0032 at each time); 20 mg/kg trend did not reach significance[3]
Relative CSF APLP1β17, β18 and β28 signalsWithin-dose longitudinal comparison At 80 mg/kg, β17 and β18 were higher at 4 h than 8 h (p = 0.027 and 0.016). β28 increased at 8 h versus predose (p = 0.0032); 8 h versus 24 h: p = 0.0032 (80 mg/kg) and p = 0.047 (20 mg/kg)[3]
Nonsignificant endpoints and assay limitsNegative findings No significant deviations for β21/β22 at either dose; β27 decrease remained nonsignificant at either dose; no significant β17/β18 response at 20 mg/kg[3]

Conditions shared by the study groups

Route
Oral, compound added to liquid meal
Frequency
Single administration per dose period
Treatment course
Predose and 4, 8 and 24 h CSF sampling; dose periods at least 1 week apart
Vehicle
Liquid meal (Convalescence support)
Study groups and reported outcomes
Group / doseComparatorObserved resultReference
20 mg/kg E2012Within-animal predose CSF baseline; no separate vehicle-only period described in the read experimental-animals sectionβ17/β18, β21/β22 and β27 changes not significant; β25 reduction trend not significant. β28 at 8 h exceeded 24 h (p = 0.047), without a significant predose comparison.[3]
80 mg/kg E2012Within-animal predose CSF baseline; no separate vehicle-only period described in the read experimental-animals sectionβ25 decreased at 4 and 8 h; β28 increased at 8 h. β17/β18 at 4 h exceeded 8 h. β21/β22 and β27 findings were not significant.[3]
20 mg/kg E2012
Model: Seven male beagle dogs, age 6–8 years; randomized cross-over
Reported limits: No absolute peptide concentration measurement; no separate vehicle-only comparator described.
80 mg/kg E2012
Model: Seven male beagle dogs, age 6–8 years; randomized cross-over
Reported limits: No absolute peptide concentration measurement; no separate vehicle-only comparator described.
Methods and source locations

Compound reported in the paper: E2012; Compound label in the paper: E2012 (parent compound)

Applies to the E2012 material reported in this paper; does not validate an Adooq lot or establish salt equivalence.

Figure 4a–g; Results: Modulation of APLP1 processing by E2012 in dogs; Chemicals, Experimental animals, immuno-affinity MS and statistics

Relative CSF APLP1β25 signal after 80 mg/kg: MALDI-TOF/TOF peak areas normalized to measured peptide signal, then compared with predose. Mean, n = 7, 95% CI; Friedman test with Dunn correction. — Figure 4e and Results paragraph beginning Four hours after administration

Relative CSF APLP1β17, β18 and β28 signals: Same relative-signal assay and statistics; β17/β18 significance is 4 h versus 8 h, not an asserted baseline contrast. — Figure 4a,b,g and Results: Modulation of APLP1 processing

Nonsignificant endpoints and assay limits: Relative ionization-dependent signal does not establish absolute CSF concentration; duplicate MS measurements averaged, n = 7 dogs. — Figure 4a–d,f and Results; Discussion limitations

20 mg/kg E2012 · Figure 4a–g; Results: Modulation of APLP1 processing by E2012 in dogs; Chemicals, Experimental animals, immuno-affinity MS and statistics

80 mg/kg E2012 · Figure 4a–g; Results: Modulation of APLP1 processing by E2012 in dogs; Chemicals, Experimental animals, immuno-affinity MS and statistics

Specifications

Manufacturer Adooq Bioscience
Actions Inhibitor
CAS Number 870843-42-8
Applications gamma-secretase modulator
Formula C25H26FN3O2
Molecular Weight 419.49
SMILES
CC1=CN(C=N1)C2=C(C=C(C=C2)/C=C/3\CCCN(C3=O)[C@@H](C)C4=CC=C(C=C4)F)OC

Storage & Solubility

In Vitro Solubility

Reported Solubility

No reported solubility data are available for this product.

Preparing Stock Solutions

Stock preparation is unavailable for this product molecular weight.

Calculated stock concentrations do not establish solvent solubility. Refer to the reported solubility data for experimental guidance.

Storage

Store powder at -20°C, keep desiccated.
In powder form, the chemical is stable for 36 months.
In solution, store at -20°C and use within 1 month to prevent loss of potency. Aliquot to avoid multiple freeze/thaw cycles.

Research References

  1. [1] Cai T, Yonaga M, Tomita T. Activation of γ-Secretase Trimming Activity by Topological Changes of Transmembrane Domain 1 of Presenilin 1. J Neurosci (2017). PMID: 29118109 DOI: 10.1523/jneurosci.1628-17.2017 Source material
  2. [2] Weber TA, Lundkvist J, Wanngren J, et al. γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing. J Cell Mol Med (2022). PMID: 34931449 DOI: 10.1111/jcmm.17146 Source material
  3. [3] Sjödin S, Andersson KK, Mercken M, et al. APLP1 as a cerebrospinal fluid biomarker for γ-secretase modulator treatment. Alzheimers Res Ther (2015). PMID: 26689589 DOI: 10.1186/s13195-015-0160-z Source material

Publications

1 publication citing this product

  1. Yesuvadian R, .et al. , Biochem Biophys Res Commun., 2014, May 16;447(4):590-5 PMID: 24747079

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