# Development of selective calpain-1 inhibitors for chronic pain

> **NIH NIH R41** · 1910 GENETICS INC. · 2021 · $546,376

## Abstract

PROJECT SUMMARY
Never in the history of the United States has the unmet medical need to develop novel, non-opioid
therapeutics for chronic pain been more urgent than it is today. More than 65 million US adults suffer from
chronic pain, resulting in almost $635 billion in annual healthcare costs. Despite their limited efficacy, and
potential for addiction, tolerance, and impaired motor performance, opioids have become a mainstay for
chronic pain management, resulting in an opioid epidemic that is ravaging communities throughout the US.
Thus, there is an urgent need to develop novel, non-opioid therapies for chronic pain management. This
application addresses this unmet medical need by leveraging our novel artificial intelligence (AI)-driven
drug discovery platform to develop selective inhibitors of calpain-1 as novel non-opioid therapeutics for
chronic pain. Studies in chronic neuropathic pain animal models have shown that nerve injury overactivates
calpain-1, which downregulates K+ Cl- cotransporter activity, resulting in diminished synaptic inhibition
and neuropathic pain. Prior work by our group has also shown that both pharmacological inhibition and
whole body genetic knockout of calpain-1 attenuates chronic pain behaviors in mouse models of sickle cell
disease (SCD). Importantly, the analgesic effect of calpain-1 inhibition did not induce tolerance side effects,
suggesting the potential for calpain-1 inhibitors to be non-addictive. By applying our innovative artificial
intelligence (AI)-driven drug discovery platform to screen a virtual chemical library, we identified four (4)
novel calpain-1 inhibitors, and validated them for efficacy in biochemical assays. Here, we propose to
progress our most potent hit compound to a lead compound that is calpain-1 selective, cysteine protease
family selective, non-opioid, and CNS penetrant with efficacy demonstrated in at least 1 of 3 chronic pain
animal models tested, including chronic sickle cell disease pain, chronic inflammatory pain, and chronic
neuropathic pain. Three aims are proposed, including Aim 1: Synthesize ~100 analogs of our most potent
hit compound, and characterize in vitro activity and selectivity. Success criteria: Top 20 cell-permeable,
calpain-1 inhibitors, moderately selective against calpain-2, and highly selective against cathepsins and
caspase-1, Aim 2: Evaluate ADME-Tox and PK profile of our top 20 calpain-1 inhibitors from Aim 1.
Success criteria: Top 2 CNS-penetrant selective calpain-1 inhibitors with favorable in vivo PK profile, and
Aim 3: Determine the efficacy and PK/PD relationship of our top calpain-1 inhibitor in 3 chronic pain
animal models. Success: at least 40% reduction in mechanical hyperalgesia in at least 1 of the 3 chronic
pain animal models tested. Successful completion of this Phase I will yield a novel CNS-penetrant, selective
calpain-1inhibitor with efficacy demonstrated in at least 1 chronic pain animal model. Our overall product
would be the first, oral, CN...

## Key facts

- **NIH application ID:** 10078437
- **Project number:** 1R41NS118992-01
- **Recipient organization:** 1910 GENETICS INC.
- **Principal Investigator:** Jennifer O Nwankwo
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $546,376
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078437

## Citation

> US National Institutes of Health, RePORTER application 10078437, Development of selective calpain-1 inhibitors for chronic pain (1R41NS118992-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10078437. Licensed CC0.

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