# Inhibiting AD Inflammation with a Novel Class of Small Molecule PAI-1 Antagonists

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $431,750

## Abstract

Abstract
Alzheimer’s disease (AD) affects an estimated 5.7 million Americans, a number expected to reach 14 million by
2050. Despite several decades of research, the initiation and progression of AD continues to be poorly
understood, indicating the need for novel therapeutic strategies. There is mounting evidence that
neuroinflammation plays an important role in the progression of AD. We are proposing to investigate Cmpd
10357, a novel UCD small molecule originally developed as a highly selective anti-cancer agent, for treatment
of AD. Cmpd 10357 selectively targets intracellular protein complexes containing the serine protease inhibitor,
plasminogen activator inhibitor-1 (PAI-1). PAI-1 functions as the primary inhibitor of tissue plasminogen
activator (tPA) and urokinase (uPA). PAI-1 is not expressed in the normal brain, but its expression is markedly
increased in cytokine-activated microglia and astrocytes, and increased PAI-1 expression has been
demonstrated in AD patients and AD animal models. High levels of PAI-1 expression and secretion by
activated microglia and astrocytes inhibits plasmin activation by serine proteases and has been demonstrated
to decrease Aβ protein degradation, thereby promoting plaque formation. We hypothesize that Cmpd 10357
will selectively target and kill activated microglia and astrocytes in the AD brain that express PAI-1, thereby
slowing or preventing progression of AD via potentially two mechanisms: (i) reducing neuroinflammation;
and/or (ii) improving Aβ clearance from the brain. To test this hypothesis, we will investigate the drug’s impact
on neuroinflammatory status, AD pathology, and cognitive dysfunction in the transgenic TgF344-AD rat model.
The objectives are to determine whether weekly intraperitoneal administration of Cmpd 10357 attenuates
neuroinflammatory changes and plaque formation in the TgF344-AD rat and assess the impacts of these
changes on the progression of AD pathology and cognitive decline. This project leverages an ongoing
collaboration between the PIs that has resulted in publications characterizing the anti-inflammatory properties
and novel drug mechanisms of action of two new classes of small molecules. Consistent with the goals of the
R21 funding mechanism, this project is high risk, but if successful, high payoff in that it will generate proof-of-
concept data for a novel therapeutic candidate for AD that potentially works via both Aβ-independent and
dependent mechanisms. Findings from these studies may also validate Cmpd 10357 as a potential therapeutic
approach for other neurological diseases with a predominant neuroinflammatory component, as well as a tool
compound for addressing the controversy regarding the neuroprotective vs. neurotoxic role of microglia and
astrocytes in AD by enabling the selective death of PA1-expressing glia at specific stages in the progression of
AD in preclinical models.

## Key facts

- **NIH application ID:** 9874982
- **Project number:** 1R21AG065908-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** FREDRIC A GORIN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2020-01-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9874982

## Citation

> US National Institutes of Health, RePORTER application 9874982, Inhibiting AD Inflammation with a Novel Class of Small Molecule PAI-1 Antagonists (1R21AG065908-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9874982. Licensed CC0.

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