# Targeting biologically relevant tau monomers and oligomers using a novel DEL drug discovery platform to treat Alzheimer’s disease and tauopathies

> **NIH NIH R43** · JILLION THERAPEUTICS INC. · 2024 · $496,373

## Abstract

PROJECT SUMMARY
Targeting biologically relevant tau monomers and oligomers using a novel DEL drug
discovery platform to treat Alzheimer’s disease and tauopathies
This Phase I SBIR project aims at the identification using our novel DNA-encoded library (DEL) drug discovery
platform of small molecular weight compounds that can bind to the protein monomeric and/or oligomeric tau
and modify its biology, ultimately blocking or reducing its toxicity. A number of neurodegenerative diseases
such as Alzheimer’s disease (AD) and sporadic frontotemporal dementias (e.g., Pick’s disease), are called
tauopathies because of the abnormal intracellular inclusions highly enriched in tau protein that characterize
them. These inclusions or neurofibrillary tangles (NFTs) are believed to be the result of pathological misfolding
of tau due to hyperphosphorylation and leading to oligomerization, fibrillization and involving spreading of
soluble tau oligomers. Those facts together with the progression with age of tau pathology and the difficulty to
target Aβ peptide oligomers make the identification of tau pathology inhibitors highly relevant and urgently
needed for AD and all tauopathies in general. Tau drug discovery is hampered by the need of large amounts of
mostly non-physiological tau protein (E. coli) for high-throughput screening (HTS), the need to use elaborated
tau systems that are not HTS compatible to recapitulate tau biology, and the need for a clear tau biological
activity to perform HTS drug screening. Our research strategy is to remove those limitations and identify tau
binders using a DEL screening approach that will allow small amounts of a physiological/high quality protein
target to be used with very large screening power (125 million entirely new proprietary compounds) and a
binding-based assay that is activity-independent. The central hypothesis is that due to the very large number of
compounds available to be tested and the inherent diversity, it will be possible to identify efficiently, in a cost-
effective way, compounds that are high-affinity binders of tau oligomers and possibly protofibrils. DEL
screening protocols have been generated and optimized focusing on minimizing the amount of protein tau to
be used and on purifying tau from mammalian cells. These steps will ensure that a physiological tau version is
used for screening and validation purposes. Screen duplicates used are increasing confidence and improve
hits’ heuristic values determination. Aim 1 will be dedicated to finalizing DEL screening campaigns with
monomeric tau. Tau will be expressed in mammalian cells, purified, aggregated, and immobilized on beads.
Aim 1 will generate a list of 24-36 hits binding to monomeric tau and not found for oligomeric tau; specificity
will be investigated. Physical binding of all candidate hits identified (up to 100) will be validated with two
different methods. Aim 2 will include chemical synthesis of 18 additional new hits and intermediaries, structu...

## Key facts

- **NIH application ID:** 11005644
- **Project number:** 1R43AG085856-01A1
- **Recipient organization:** JILLION THERAPEUTICS INC.
- **Principal Investigator:** Marc Flajolet
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $496,373
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11005644

## Citation

> US National Institutes of Health, RePORTER application 11005644, Targeting biologically relevant tau monomers and oligomers using a novel DEL drug discovery platform to treat Alzheimer’s disease and tauopathies (1R43AG085856-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11005644. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*