# Inhibitors of TrkB Signaling

> **NIH NIH R33** · DUKE UNIVERSITY · 2022 · $211,955

## Abstract

Abstract
 Temporal lobe epilepsy (TLE) is a common and often devastating form of human epilepsy that currently
lacks preventive or disease modifying therapy. Evidence from clinical and preclinical studies supports the idea
that an episode of prolonged seizures (status epilepticus or SE) contributes to development of TLE. Defining
the molecular mechanisms by which SE transforms a normal brain into an epileptic brain can identify molecular
targets for preventive therapies. We conducted an extensive series of target validation experiments and
identified a druggable molecular target that can prevent TLE in mice, namely the brain-derived neurotrophic
factor receptor tyrosine kinase, TrkB. We conducted a high-throughput screen seeking small molecule
inhibitors and have identified two broad chemotypes, each of which contains multiple chemical series. Here
we seek to enter the Discovery stage of the Blueprint Network during which we will prosecute a medicinal
chemistry effort to improve the potency and drug-like properties of promising bioactive compounds. We
propose the following Aims. Aim 1: To complete preparation for entering UH3 phase. Aim 2 (UH3 phase): To
prosecute an SAR lead optimization effort to identify a clinical candidate molecule. Aim 3 (UH3 Phase): To
conduct IND enabling studies. The lack of effective preventive and disease modifying therapies for common
disorders of the human nervous system is a glaring unmet medical need critical to the mission of NINDS. The
work proposed here represents a novel and innovative approach to develop drugs for prevention and disease
modification of TLE, a common disorder of the CNS.

## Key facts

- **NIH application ID:** 10405471
- **Project number:** 5R33NS111708-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** James O. McNamara
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $211,955
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405471

## Citation

> US National Institutes of Health, RePORTER application 10405471, Inhibitors of TrkB Signaling (5R33NS111708-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10405471. Licensed CC0.

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