# Targeting p38/MK2 protein-protein interaction to control neuroinflammation in Alzheimer's Disease

> **NIH NIH R03** · EMORY UNIVERSITY · 2024 · $313,000

## Abstract

Alzheimer's disease (AD) is the most common cause of dementia and one of the leading causes of death
worldwide. The current failure in AD therapeutic development demands the discovery of new therapeutically
actionable mechanisms underlying the disease. To address this unmet medical need, we propose to define the
protein-protein interaction between p38 and MK2 as a highly promising target to control neuroinflammation, one
of the major hallmarks of Alzheimer’s disease. The protein-protein interaction between mitogen-activated protein
kinase p38 and its main substrate MK2 plays a central role in pro-inflammatory signaling. Both proteins are well-
defined targets for therapeutic discovery, and multiple inhibitors have been proposed to control
neuroinflammation by inhibiting p38 or MK2 kinase activity. However, none of the proposed inhibitors have
reached the approval as a drug. The commonly recognized reasons for such failure include multiple adverse
side effects associated with i) network effects of p38 inhibition on multiple p38-regulated proteins besides MK2
and ii) limited compound selectivity against other kinases. Thus, targeting p38 and MK2 individually cannot
provide an efficient strategy to control neuroinflammation in AD. We propose to overcome this critical barrier
by discovering small molecules to disrupt the protein-protein interaction between p38 and MK2 proteins
rather than inhibit their kinase activity. The unique physical and chemical properties of the protein-protein
interaction interface allow us to design highly specific compounds to precisely regulate the p38/MK2 complex
avoiding the undesired interference with other axes of p38 signaling or other kinases. Toward this goal, we have
established a robust high-throughput screening assay and a computational platform that already revealed the
first small molecule and peptide-based disruptors of the p38/MK2 complex. Previously, we successfully applied
our approach to discover small molecule inhibitors and stabilizers of disease-associated protein complexes of
different types. We hypothesize that the inhibition of protein-protein interaction (PPI) between p38 and MK2
represents a novel promising strategy to control p38/MK2-dependent neuroinflammation in AD. To test this
hypothesis, we will combine experimental high-throughput screening (HTS) with computational modeling to
discover the first small molecule inhibitors of the p38/MK2 complex and demonstrate that p38/MK2 PPI inhibition
can suppress pro-inflammatory signals and rescue AD phenotypes in cortical organoids. The completion of this
study will establish the p38/MK2 interaction as a novel druggable target to control neuroinflammation, provide
the first small molecules to regulate this pathogenic complex, and may enable new clinical strategies in
Alzheimer's disease.

## Key facts

- **NIH application ID:** 10889827
- **Project number:** 1R03AG087482-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** ANDREY IVANOV
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $313,000
- **Award type:** 1
- **Project period:** 2024-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889827

## Citation

> US National Institutes of Health, RePORTER application 10889827, Targeting p38/MK2 protein-protein interaction to control neuroinflammation in Alzheimer's Disease (1R03AG087482-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10889827. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*