# TREAT AD Medicinal Chemistry Core

> **NIH NIH U54** · EMORY UNIVERSITY · 2024 · $1,114,709

## Abstract

PROJECT SUMMARY MEDICINAL CHEMISTRY CORE
The Emory-Sage-SGC-Jax TREAT-AD Center Medicinal Chemistry (MedChem) Core, led by Dr. Alison
Axtman, aims to contribute a key component of Target Enabling Packages (TEPs): a small molecule. At
minimum, this small molecule will represent a chemical starting point, validated to bind to its target, in need of
further optimization in terms of on-target potency and proteome-wide selectivity. Ideally, this small molecule will
prove suitable for optimization by the MedChem Core into a chemical probe that can be shared with the
scientific community to interrogate and vet poorly characterized AD protein targets. The track record of the
Axtman lab, which is part of the Structural Genomics Consortium (SGC), supports that delivery of chemical
probes is both feasible and routinely executed for a variety of targets.
Purified protein and assays developed by the Structural Biology Core (StrucBio Core) will enable the
MedChem Core to engage in hit discovery, specifically employing DNA-encoded library screening with
machine learning (DEL/ML) as part of novel public-private partnerships with XChem and other partners (Open
DEL/ML, Aim 1). As part of a unique approach, Open DEL/ML will deposit previously proprietary DEL
screening data into the public domain in an ML-enabling format, enabling the community to build models of “hit
space” and to use the models to predict commercially-available drug-like hits. Access to purified protein and
assays will also facilitate characterization of putative hit compounds within the MedChem Core. The
physicochemical properties of these small molecules will be assessed in tandem (Aim 2). Finally, if a confirmed
hit has physicochemical properties to support its optimization, the MedChem Core will iteratively design sets of
drug-like analogs and evaluate them using a hierarchy of embedded assays to probe target affinity, selectivity,
cellular activity, and in vitro ADME properties. Chemical probes that achieve the desired activity in these
assays will advance into in vivo assessment of plasma/brain PK and target engagement, and will be
considered for advancement to models of AD. Compounds that proceed to hit to probe optimization are likely
amongst the best available for a given protein target and thus would be great candidates for inclusion in the AD
Informer Set (Aim 3).
The specific aims of the MedChem Core are:
 1. Hit discovery
 2. Hit characterization
 3. Hit to probe optimization

## Key facts

- **NIH application ID:** 10954116
- **Project number:** 2U54AG065187-06
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** ALLAN I LEVEY
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,114,709
- **Award type:** 2
- **Project period:** 2019-09-30 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10954116

## Citation

> US National Institutes of Health, RePORTER application 10954116, TREAT AD Medicinal Chemistry Core (2U54AG065187-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10954116. Licensed CC0.

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