# Targeting Postsynaptic Small G-protein Regulators

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $705,846

## Abstract

ABSTRACT
This application aims to discover and validate small-molecule inhibitors of the Rac guanosine-nucleotide
exchange factor (GEF) kalirin, a major signal transduction hub in dendritic spines in the cerebral cortex.
Our long-term goal is to translate knowledge about dendritic spine plasticity and synaptic small GTPase
signaling, into treatments of neuropsychiatric disorders (NPDs). Dendritic spines are the sites of most
excitatory synapses in the brain, and play central roles in the development and plasticity of neuronal circuits,
and ultimately in learning, memory, and behavior. Conversely, abnormalities in dendritic spines are
extensively involved in NPD pathogenesis. Molecular pathways mediated by small GTPases such as Rac,
direct upstream activators (GEFs), and their downstream targets are major pathways that govern dendritic
spine plasticity. Furthermore, genetic and postmortem studies demonstrate a key role for these pathways
in the pathogenesis of NPDs. Kalirin is the most abundant Rac-GEF in dendritic spines in the cerebral cortex
and hippocampus, plays central roles in spine plasticity and pathology as shown by knockdown and
knockout studies, and has been implicated in NPDs by genetic, postmortem, and functional studies. Hence,
in order to study the role of kalirin in cortical plasticity and NPD pathogenesis, and of Rac-GTPase signaling
in general, here we aim to develop novel, potent, specific, inhibitors of kalirin with biological activity in
neurons. We have established a collaboration between experts in synapse biology and NPDs, high-
throughput screening and computational pharmacology, medicinal chemistry, and crystallography, and
performed extensive preliminary studies that demonstrate the validity of our hypothesis and the feasibility
of our approach. We propose the following Specific Aims: 1) Hit discovery by HTS to identify small
molecules binding to kalirin's DHPH domain and inhibiting its GEF activity. 2) Hit validation in cellular
and neuronal assays. 3) Characterization of the mechanism of action of hit compounds. 4) Medicinal
chemistry optimization of new GEF inhibitors

## Key facts

- **NIH application ID:** 10867469
- **Project number:** 5R01MH130838-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** CHI-HAO LUAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $705,846
- **Award type:** 5
- **Project period:** 2022-07-19 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867469

## Citation

> US National Institutes of Health, RePORTER application 10867469, Targeting Postsynaptic Small G-protein Regulators (5R01MH130838-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10867469. Licensed CC0.

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