# Discovering Small Molecule Activators of Stress-responsive Signaling

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $601,723

## Abstract

The maintenance of secreted protein homeostasis, or proteostasis, involves balancing protein biosynthesis,
translocation across membranes, folding, degradation, etc., which we hypothesize is critical for healthy aging.
Since the demands on secretory compartments to maintain proteostasis change with development, aging, and
environmental stresses, mammals evolved the Unfolded Protein Response (UPR) stress-responsive signaling
pathway, which transcriptionally adjusts secretory proteostasis network capacity to meet demand. Recent
human genetic, chemical biologic, and in vivo evidence shows that activating the protective IRE1/XBP1s or
ATF6 arms of the UPR has significant promise to ameliorate age-related declines in secretory proteostasis and
correct imbalances associated with etiologically-diverse diseases, including systemic amyloid diseases,
cardiovascular disorders, diabetes, and neurodegenerative diseases such as Alzheimer's disease and
Parkinson's disease. Few compounds exist to achieve arm-selective UPR activation, and those that do suffer
from limitations that prevent their translational development. We have leveraged cell-based transcriptional
reporter assays miniaturized for high-throughput screening (HTS), along with whole cell transcriptional and
proteomic profiling to understand the selectivity of the transcriptional and translational response generated by
our screening hits. We have elaborated promising compounds using medicinal chemistry to establish first-in-
class small molecule `proteostasis regulators' that selectively activate the protective IRE1/XBP1s or ATF6
signaling arms of the UPR with improved potency and selectivity, and we seek their mechanism of action
through multiple approaches. We will assess whether our proteostasis regulators can induce protective, arm-
selective UPR activation in young and old animals. We have established collaborations to test the hypothesis
that our IRE1/XBP1s and ATF6 activators will be useful for ameliorating pathologic imbalances in secretory
proteostasis associated with multiple diseases, including the systemic amyloidoses, degenerative eye
diseases, cardiovascular disease, and neurodegenerative disorders. Furthermore, we will show that these
compounds pharmacologically ameliorate two pathologic phenotypes associated with Alzheimer's disease in
cell culture models: i.e., the pathologic production of Aβ and Aβ oligomer-associated neuronal cytotoxicity. We
will deliver to the scientific community the first well-characterized small molecules that preferentially activate
the IRE1/XBP1s or the ATF6 UPR transcriptional programs with a defined potency and selectivity. These
compounds have the potential to be widely employed as therapeutics for a spectrum of age-associated
diseases. Importantly, these compounds will be made available to all scientists with disease models wherein
pharmacologic IRE1/XBP1s or ATF6 activation has the potential to influence pathogenesis. The availability of
these compounds ...

## Key facts

- **NIH application ID:** 9904304
- **Project number:** 5R01AG046495-08
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** JEFFERY W KELLY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $601,723
- **Award type:** 5
- **Project period:** 2013-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904304

## Citation

> US National Institutes of Health, RePORTER application 9904304, Discovering Small Molecule Activators of Stress-responsive Signaling (5R01AG046495-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9904304. Licensed CC0.

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