E2012

E2012 is a modulator of γ-secretase.¹ It selectively inhibits APP intracellular signaling domain (AICD) cleavage to amyloid-β (Aβ) over Notch cleavage to its signaling effector Notch intracellular domain (NICD), processes both mediated by γ-secretase, when used at a concentration of 1 µM in luciferase assays.² E2012 also inhibits the activity of the cholesterol synthesis enzyme 3β-hydroxysterol ∆²⁴-reductase (DHCR24) in primary rat hepatocytes and HepG2 cells (IC₅₀s = 11 and 15 nM, respectively).³ It reduces Aβ (1-42) (Aβ42) production in primary rat embryonic cerebral cortex neurons with an IC₅₀ value of 220 nM.⁴ E2012 (100 mg/kg) also decreases Aβ42 levels in guinea pig brain and cerebral spinal fluid (CSF).⁴

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1. Hahn, S., Brüning, T., Ness, J., et al. Presenilin-1 but not amyloid precursor protein mutations present in mouse models of Alzheimer’s disease attenuate the response of cultured cells to γ-secretase modulators regardless of their potency and structure. J. Neurochem. 116(3), 385-395 (2011).

2. Dimitrov, M., Alattia, J.-R., Lemmin, T., et al. Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production. Nat. Commun. 4:2246, (2013).

3. Nakano-Ito, K., Fujikawa, Y., Hihara, T., et al. E2012-induced cataract and its predictive biomarkers. Toxicol. Sci. 137(1), 249-258 (2014).

4. Kimura, T., Kawano, K., Doi, E., et al. Cinnamide compound. (2005).