# Targeting Necroptosis for Neurodegenerative Disease Therapy

> **NIH NIH R41** · REGENERIX LLC · 2021 · $449,594

## Abstract

PROJECT SUMMARY/ABSTRACT
The long-term objective of the project is to develop therapeutics for Alzheimer’s that inhibit a unique method of
cell death known as necroptosis. This cell death pathway has been known to be upregulated in
neurodegenerative diseases, highlighting the need to find therapeutics that target the proteins involved. Several
kinases are known to be important regulators that include: RIPK1, RIPK3 and MLKL. However, unlike most
therapeutic approaches that target the kinase portion of RIPK proteins involved in necroptosis, we are targeting
the protein-protein interface between RIPK3 and MLKL. This targeting method should uncover more specific
compounds since RIPK kinases are involved in multiple pathways. By targeting an interface that is only shared
between two proteins involved in necroptosis (protein-protein interface), we ensure that there are fewer side
effects as compared to targeting the kinase function implicated in more than just necroptosis. It was previously
shown that an interaction between RIPK3 and MLKL located away from the kinase interface is necessary to
promote RIPK3 and MLKL binding. We targeted in silico this pocket that is involved in the interaction of RIPK3
to MLKL using a library of small molecules. The top 13 compounds were tested using flow to assay of cells where
apoptosis is inhibited and cells only undergo cell death through necroptosis. Using this assay, we were able to
narrow down the list of compounds to two hits that specifically inhibit necroptosis, we showed the compounds
are targeting the RIPK3 protein in cells. Follow-up studies with derivatives of these two hit compounds exhibited
improvements. We propose to further develop compounds using chemical synthesis and test the compounds
using patient-derived stem cells for improvements in cellular assays. These new derivative compounds should
create a more extensive SAR and will be the next generation compounds to develop more lead-like compounds
for AD therapeutics.

## Key facts

- **NIH application ID:** 10253999
- **Project number:** 1R41AG069606-01A1
- **Recipient organization:** REGENERIX LLC
- **Principal Investigator:** May Khanna
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $449,594
- **Award type:** 1
- **Project period:** 2021-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10253999

## Citation

> US National Institutes of Health, RePORTER application 10253999, Targeting Necroptosis for Neurodegenerative Disease Therapy (1R41AG069606-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10253999. Licensed CC0.

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