# Mechanism and Synergy  of gamma-Secretase Modulators

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $428,500

## Abstract

   
DESCRIPTION (provided by applicant): The overall objectives of this proposal are to elucidate the mechanism of action of different classes of next generation γ-secretase modulators (GSMs), to determine their synergistic effect, and to apply them in examining the role of Aβ42, Aβ38 and Aβ37 in amyloid pathology, synaptic plasticity and learning and memory. The development of GSMs that suppress γ-secretase activity for Aβ42 production and yet do not affect overall APP processing and cleavages of other substrates has emerged as a promising strategy for AD therapy. Progress in the development of these clinical candidates depends on a deeper understanding of the drug-target interactions. To this end we propose to map the binding site of acid GSMs within the γ-secretase complex and to investigate the structural basis of γ-secretase modulation. Additionally, we will determine the mechanism of cooperatively between the γ-secretase active site and the imidazole based GSM binding site(s). Finally, we will examine the synergistic effect of two classes of GSMs in cellular and animal models with a focus on safety, synaptic plasticity and learning and memory. The proposed research will provide mechanistic insights into GSM modulation of γ-secretase, the function of Aβ in disease and new therapeutic strategies, shaping our understanding of GSM selectivity and advancing our ability to design effective treatment.

## Key facts

- **NIH application ID:** 9918989
- **Project number:** 5R01NS096275-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** YUEMING LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $428,500
- **Award type:** 5
- **Project period:** 2016-06-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918989

## Citation

> US National Institutes of Health, RePORTER application 9918989, Mechanism and Synergy  of gamma-Secretase Modulators (5R01NS096275-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9918989. Licensed CC0.

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