# Activation of TGFb signaling using novel SMAD4 molecular glues

> **NIH NIH R37** · EMORY UNIVERSITY · 2024 · $357,994

## Abstract

SUMMARY
Alzheimer’s disease (AD) is a neurodegenerative disease, leading to memory and cognitive impairment.
Neuroinflammation has been identified as a prominent hallmark of AD. Neuroinflammation encompasses a
variety of inflammatory events. The process is marked by the production of pro-inflammatory cytokines, and
suppression of anti-inflammatory cytokines. These dysregulated cytokines orchestrate with microglia, astrocyte
and neuronal cells and contribute to the accumulation of Ab and tau, and neuronal injury. Therefore, therapeutic
strategies that may intervein the neuroinflammation process hold significant promise for AD treatment.
Transforming Growth Factor beta (TGFβ) is a pluripotent anti-inflammatory cytokine that has long been
implicated in the pathogenesis of AD. TGFβ-SMAD signaling-mediated regulation occurs at the level of neuronal
survival and differentiation, microglia activation, amyloid production-distribution-clearance cycles, and
neurofibrillary tangle formation, all of which contributes to AD’s pathophysiology. Therefore, the TGFβ-SMAD
signaling represents a novel promising target for therapeutic innovation. However, there is no successful attempt
to reinstall the impaired TGFβ-SMAD signaling. Recently, we have identified a panel of novel small molecules
as molecular glues that can stabilize the SMAD3-SMAD4 transcriptional complex and thus activate the TGFβ-
SMAD signaling. Our preliminary studies demonstrate that these novel SMAD3-SMAD4 molecular glues can 1)
stabilize the protein-protein interaction (PPI) between SMAD4 and SMAD3, 2) activate SMAD3-SMAD4
transcriptional activity in luciferase reporter assays, 3) stimulate TGFβ-SMAD signaling target gene expression,
and 4) promote corresponding cellular phenotypes. Based on these strong scientific premises, we hypothesized
that the impaired TGFβ-SMAD signaling in AD patients can be reinstalled using novel SMAD3-SMAD4 molecular
glues, which could serve as innovative therapeutic strategy to re-establish TGFβ-mediated anti-inflammatory
milieu and mitigate AD pathological symptoms. We will determine the effect of SMAD3-SMAD4 molecular glues
in primary and human iPSC-derived microglia cells model (Aim 1) and in neuroblastoma and human iPSC-
derived neurons and organoids model (Aim 2). Accomplishing the proposed studies is expected to identify a
novel therapeutic strategy with SMAD3-SMAD4 molecular glues to reinstall the impaired TGFβ-SMAD signaling
in microglia and neuronal cells, and thus reset the neuro-immune homeostasis for AD patients.

## Key facts

- **NIH application ID:** 10939445
- **Project number:** 3R37CA255459-04S1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Xiulei Mo
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $357,994
- **Award type:** 3
- **Project period:** 2021-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939445

## Citation

> US National Institutes of Health, RePORTER application 10939445, Activation of TGFb signaling using novel SMAD4 molecular glues (3R37CA255459-04S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10939445. Licensed CC0.

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