# Development of drugs that modify CNS innate immunity for the treatment of Multiple Sclerosis

> **NIH NIH R61** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $434,860

## Abstract

PROJECT SUMMARY
Pathology driven by resident cells in the central nervous system (CNS) such as astrocytes and microglia plays
an important role in multiple sclerosis (MS), particularly for its progressive stage which is eventually achieved
by most MS patients. However, no drugs are available for the modulation astrocyte and microglia pathogenic
activities. We developed an in vitro assay to identify compounds that modulate astrocyte pathogenic activities.
These studies identified compound A-38, an inhibitor of the Erythropoietin-producing hepatocellular
carcinoma receptor B3 (EphB3), as a suppressor of astrocyte pathogenic activities and, consequently, as a
lead therapeutic compound for progressive MS (PMS). Moreover, our data suggest that microglia-driven
EphB3 signaling in astrocytes promotes CNS inflammation and neurodegeneration. Ephrin receptors are
known to participate in CNS development, however our findings define a novel role for EphB3 in CNS
inflammation and identify it as potential target for therapeutic intervention. We hypothesize that EphB3
kinase inhibition will provide an efficacious therapeutic approach for PMS, and potentially other
neurologic diseases. Thus, we propose to develop new A-38 analogs to treat PMS. Our Specific Aims are:
SPECIFIC AIM 1: OPTIMIZATION AND IN VITRO EVALUATION OF EPHB3 KINASE INHIBITORS. We will
design, synthesize and evaluate the properties of up to 150 analogs of A-38. The goal of these studies is to
optimize the potency and kinase selectivity of new analogs of A-38, while maintaining good drug-like properties
and brain exposure following oral delivery. During the R61 phase of this project, we will integrate iterative
structure-activity relationship (SAR) studies and structure based drug design to optimize A-38 potency and
kinase selectivity, while maintaining good drug-like properties. We will first evaluate A-38 analogs for EphB3
activity and for selectivity in EphB2 EphB4, and EphA4 kinase assays. Promising compounds will advance to
phenotypic assays to identify those molecules that modulate astrocyte pathogenic activities. Compounds of
interest will then be characterized in drug-like property assays to select leading compounds for PO PK studies.
At the end of the R61 phase of this project we expect to identify a lead EphB3 inhibitor and 1-2 back-ups
suitable for advancement into in vivo efficacy testing in the R33 phase.
SPECIFIC AIM 2: EVALUATION OF LEAD COMPOUND(S) IN PMS PRE-CLINICAL MODELS. During the
R33 phase of this project, we will evaluate the lead EphB3 inhibitor and 1-2 back-ups in the NOD EAE and
cuprizone-induced murine pre-clinical models which recapitulate several aspects of PMS. We will evaluate
the effects of the compounds on disease development, CNS inflammation, axonal loss and demyelination, as
determined by histopathology, flow cytometry and gene expression analyses.
In summary, this project will identify a novel EphB3 inhibitor with drug-like properties suitable for developmen...

## Key facts

- **NIH application ID:** 10434315
- **Project number:** 1R61NS114383-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Kevin Hodgetts
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $434,860
- **Award type:** 1
- **Project period:** 2022-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434315

## Citation

> US National Institutes of Health, RePORTER application 10434315, Development of drugs that modify CNS innate immunity for the treatment of Multiple Sclerosis (1R61NS114383-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10434315. Licensed CC0.

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