# Targeting the EPhA4 in motor neuron disease: a structure-based approach

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $451,694

## Abstract

Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons.
Mutations in the gene SOD1 (superoxide dismutase 1) and in chromosome 9 seem the most prevalent
in those affected by the disease. Despite tremendous efforts aimed at identifying contributing factors
for ALS, the mechanisms underlying motor neuron death have not yet been fully elucidated and
consequently no effective treatment is currently available for ALS. Several clinical trials have been
initiated based on drugs selected from animal studies, however, these ultimately failed. Obviously
among the possible reasons for such failures, is the lack of a proper drug target responsible for the
onset and progression of ALS. In this regard, numerous recent studies clearly suggest the EphA4 is a
potential drug target for ALS and that targeting its ligand–binding domain may provide a possible
avenue to novel and effective therapeutics. Based on these premises, we have recently designed and
synthesized a novel EphA4 binding agent, named 123C4, targeting its ligand binding domain 123C4
exhibits nanomolar affinity for the EphA4 receptor with > 10 fold selectivity over the closest receptor of
the family (EphA3), are brain penetrant and show notable efficacy in a SOD1 mutant mouse model of
ALS. Our studies aimed at further optimizing and characterizing this series will provide critical insights
on the role of the EphA4 modulation in the progression of ALS, and the data gathered in this study will
be critical in supporting the development of these agents into innovative targeted therapeutics for ALS.

## Key facts

- **NIH application ID:** 9977007
- **Project number:** 5R01NS107479-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Maurizio Pellecchia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,694
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977007

## Citation

> US National Institutes of Health, RePORTER application 9977007, Targeting the EPhA4 in motor neuron disease: a structure-based approach (5R01NS107479-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9977007. Licensed CC0.

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