# Characterizing the roles of novel soluble GSMs in AD pathology.

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $425,945

## Abstract

AD is a neurodegenerative disorder and the primary cause of dementia. Currently there is no cure for this
devastating disorder. The pathology of AD is characterized by two distinctive hallmarks: the β-amyloid plaques
primarily comprised of a small protein, amyloid-β (Aβ)1-3, and the neurofibrillary tangles composed of the
hyperphosphorylated tau protein. Aβ is produced via a serial cleavage of the amyloid-β precursor protein
(APP) through β- and γ-secretase. The aggregation-prone Aβ42 peptide is essential to AD pathology and more
prevalent than other Aβ species in cerebral β-amyloid plaques. Thus, we have focused on developing a
compound that may preferentially decrease Aβ42 levels and be an effective therapeutic for AD. We discovered
a class of γ-secretase modulators (GSMs), a group of small molecules that specifically modulate γ-secretase
cleavage in APP and thus preferentially lower Aβ42 levels without altering cleavage of other γ-secretase
substrates, e.g. Notch. Recently, we generated a novel class of pyridazine-based soluble GSMs (SGSMs), with
strong potency in lowering Aβ42 levels and high aqueous solubility. So far our best lead compound is
SGSM15606, which displays outstanding potency in lowering Aβ42 levels (IC50 = 7 nM in cell-based studies). It
also has excellent pharmacokinetics and pharmacodynamics properties including excellent oral bioavailability,
long terminal half-life and low clearance. SGSM15606 is being prepared for an Investigational New Drug
application enabling for a Phase-IA AD clinical trial (single ascending dose). Now over a hundred analogues of
SGSM15606 have been made and have yet to be tested as backups for the forthcoming clinical trials. We
hypothesize that we will be able to characterize the effects of these molecules on AD pathology to identify an
ideal compound more favorable than SGSM15606. Notably, our studies focused on disease pathology in
preclinical studies will enhance the success of candidate molecules in potential clinical trials. Specifically, we
will first use two-dimensional (2D) AD cell models to characterize and prioritize GSM15606 and analogs that
preferentially decrease Aβ42 levels (Aim 1; Years 1-2). We then will study the prioritized compounds on β-
amyloid pathology and tau pathology using our novel 3D human neural cell cultures of AD (Aim 2; Years 2-3).
Finally, we will identify the top compounds that can both acutely and chronically attenuate AD pathology using
the well-characterized AD transgenic Tg2576 mice (Aim 3; Years 4-5). Collectively, the results of the proposed
studies should not only identify the final and ultimate compound for an AD clinical trial, but also should
enhance our understanding of the biology of γ-secretase and the pathogenesis of AD.

## Key facts

- **NIH application ID:** 9850181
- **Project number:** 5R01AG055784-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Can Martin Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,945
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850181

## Citation

> US National Institutes of Health, RePORTER application 9850181, Characterizing the roles of novel soluble GSMs in AD pathology. (5R01AG055784-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9850181. Licensed CC0.

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