Our Science

Satori is developing potent, selective modulators of gamma secretase (γ-secretase) that selectively reduce the production of amyloid beta (Aß) 42, while sparing other gamma substrates. This selectivity and expected safety profile provide the opportunity for Satori’s lead compounds to treat patients in early-stage disease, potentially slowing or stopping the disease, before major brain damage or onset of clinical symptoms.
The amyloid hypothesis of Alzheimer’s disease (AD) pathophysiology postulates that Aβ, particularly the Aβ42 isoform, initiates a neurotoxic cascade that leads to amyloid deposition, neurodegeneration and cognitive decline (1). Aβ species are formed through a series of enzymatic cleavages of the Amyloid Precursor Protein (APP), initially by either alpha secretase (α-secretase) or beta secretase (β-secretase).   The product of β-secretase cleavage is cleaved further by γ-secretase to produce the neurotoxic Aβ42 peptide (2). The central role of Aβ deposition in AD pathogenesis has been further underscored by the biomarker studies complete by the North American Alzheimer's Diseases Neuroimaging Initiative (ADNI) (3). These, along with other studies, have created an environment where gamma secretase modulation is widely accepted as the industry’s best target for preventing the production of toxic Aβ.

Given its central role in the amyloid hypothesis, inhibition of γ-secretase has the potential to be a disease-modifying, and possibly preventive, treatment for AD (4). However, non-selective inhibitors of γ-secretase carry mechanism-based safety concerns, as they also prevent processing of other physiologically relevant γ-secretase substrates, including Notch (4). Recently, a non-selective γ-secretase inhibitor, LY450139, was discontinued in Phase 3 clinical development because of such non-specific adverse events.

Satori’s medicinal chemistry and in vitro screening assays have led to the identification of novel, potent small molecules with confirmed modulating γ-secretase activity.  These compounds display the selectivity and drug-like properties required for the successful, chronic dosing of CNS- acting drugs targeting γ-secretase. 

1. Hardy J and Selkoe DJ.  The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics.  Science, 297: 353-356, 2002.
2. Thinakaran G and Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem, 283:29615-29619, 2008.
3. ADNI website: http://adni.loni.ucla.edu.
4. Bergmans BA and DeStrooper B. g-secretase: from cell biology to therapeutics strategies. Lancet Neurology, 9:215-226, 2010.

Satori Pharmaceuticals Incorporated
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Cambridge, MA 02139

Tel: (617) 547-0022
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