# Discovering Small Molecule Activators of Stress-Responsive Signaling

> **NIH NIH RF1** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $2,621,070

## Abstract

PROJECT SUMMARY
Endoplasmic reticulum (ER) stress is implicated in the onset and pathogenesis of diverse age-related diseases,
including many neurodegenerative disorders. In these diseases, ER stress leads to disruptions in nearly all
aspects of cellular physiology. To protect tissues against ER stress, mammals evolved the unfolded protein
response (UPR) – a stress-responsive signaling pathway comprising three signaling arms activated downstream
of the ER membrane stress-sensing proteins IRE1, ATF6, and PERK. In response to ER stress, these pathways
are activated to promote transcriptional remodeling of multiple biological pathways to both mitigate the initiating
ER insult and prevent pathologic disruptions in cell physiology. This remodeling is primarily mediated by the
UPR-associated transcription factors XBP1s (activated downstream of IRE1) and ATF6 (a cleaved product of
full-length ATF6). These transcription factors regulate expression of genes involved in protective biological
pathways including those effecting cell metabolism, lipid regulation, redox, and secretory proteostasis. However,
despite the efficacy of the UPR in protecting cells against pathologic ER stress, deficiencies in UPR signaling
induced by genetic, environmental, or aging-related insults impair the ability of tissues to adapt their physiology,
directly contributing to tissue-specific pathologies implicated in many different types of disease. This suggests
that selective enhancement of adaptive, protective UPR signaling represents a potential opportunity to mitigate
ER stress-associated pathologies implicated in aging and age-related diseases. Consistent with this, genetic,
chemical biologic, and in vivo evidence shows that enhancing protective IRE1/XBP1s or ATF6 signaling corrects
tissue-specific pathologies implicated in many different maladies. We hypothesize that selective,
pharmacological activation of protective IRE1/XBP1s or ATF6 signaling represents a promising
therapeutic strategy to mitigate pathologies in aging and numerous age-related diseases. Over the
previous funding period, we leveraged cell-based phenotypic high throughput screening (HTS) and whole cell
transcriptional profiling to establish first-in-class compounds that selectively activate the adaptive IRE1/XBP1s
or ATF6 transcriptional signaling programs. These compounds are being used by our lab and >30 labs around
the world to define the functional implications and therapeutic potential of pharmacological IRE1/XBP1s or ATF6
activation in age-associated diseases including protein misfolding disorders, ischemia/reperfusion injury, eye
diseases, obesity-diabetes, cancer, and neurodegenerative disorders such as Alzheimer’s disease (AD). Here,
we expand this study to establish next generation compounds that selectively activate these protective UPR
pathways, through defined mechanisms of action and with improved potency, efficacy, and pharmacodynamic
and pharmacokinetic profiles, to increase their applicat...

## Key facts

- **NIH application ID:** 10599752
- **Project number:** 2RF1AG046495-11
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** JEFFERY W KELLY
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,621,070
- **Award type:** 2
- **Project period:** 2013-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599752

## Citation

> US National Institutes of Health, RePORTER application 10599752, Discovering Small Molecule Activators of Stress-Responsive Signaling (2RF1AG046495-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10599752. Licensed CC0.

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