RPI ID:
2019-075-401, 2019-076-601

Innovation Summary:
A substrate-specific inhibitor is proposed to block γ-secretase cleavage of amyloid precursor protein (APP), aiming to reduce amyloid-β (Aβ) production without affecting other physiological substrates. Unlike broad-spectrum γ-secretase inhibitors that target presenilin directly, this approach selectively targets the APPTM domain, minimizing off-target effects. The strategy leverages covalent binding mechanisms to achieve high efficacy and low dosing frequency. This method addresses the challenge of substrate promiscuity in intramembrane cleaving proteases (I-CLiPs), particularly in the context of Alzheimer’s disease.

Challenges / Opportunities:
Broad-spectrum γ-secretase inhibitors have failed in clinical trials due to adverse effects from inhibiting non-APP substrates like Notch. Targeting the substrate instead of the enzyme offers a novel therapeutic pathway with reduced toxicity. Covalent inhibitors, once avoided due to off-target concerns, are now recognized for their high efficacy and potential to address “undruggable” targets. This approach may enable selective modulation of Aβ production while preserving essential γ-secretase functions.

Key Benefits / Advantages:
✔ Selective inhibition of APP cleavage
✔ Reduced risk of side effects from Notch pathway interference
✔ High efficacy via covalent binding
✔ Lower dosage and improved patient compliance
✔ Potential to overcome failures of previous γ-secretase inhibitors

Applications:
• Alzheimer’s disease therapeutics
• Neurodegenerative disease research
• Drug discovery targeting intramembrane proteolysis

Keywords:
γ-secretase, amyloid precursor protein, Alzheimer’s disease, covalent inhibitor, intramembrane proteolysis, presenilin"

 

Issued US Patent no. 12297244

Published US Patent Application No. 19/097,101