# Targeting Diabetes With Novel SERCA Allosteric Activators

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $346,500

## Abstract

Obesity and insulin resistance are major causes of type 2 diabetes, representing an enormous
health burden to societies worldwide. Major perturbations associated with diabetes are
abnormalities in calcium homeostasis and substrate metabolism, and induction of insulin
resistance. Interestingly, disruption of endoplasmic reticulum (ER) Ca2+ levels caused primarily
by impaired function of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) has been
demonstrated to trigger ER stress in liver and β cell leading to the development of insulin
resistance in obesity and diabetes conditions. Thus, targeting dysfunctional SERCA2 will
alleviate aberrant ER stress and associated disorders in diabetes. We pharmacologically
activated SERCA2b in a genetic model of insulin resistance and type 2 diabetes (ob/ob mice)
with a novel class of small molecules that allosterically activate SERCA enzyme and rescue ER
stress-induced cell death. These compounds are amenable to optimization for potency, and
have enormous potential to treat diabetes. Studies in animal models of diabetes show
significant improvement in glucose tolerance, hepatic steatosis and metabolism, and
preservation of β-cell function and survival. Through medicinal chemistry and analoging
strategies, we aim in this proposal to conduct compound optimization of these novel series of
SERCA activators and profile them more extensively in vitro and in vivo for further development
as SERCA-based therapeutic modalities to treat diabetes and its complications.

## Key facts

- **NIH application ID:** 10573471
- **Project number:** 7R01DK111417-05
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** DJAMEL LEBECHE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $346,500
- **Award type:** 7
- **Project period:** 2022-02-16 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10573471

## Citation

> US National Institutes of Health, RePORTER application 10573471, Targeting Diabetes With Novel SERCA Allosteric Activators (7R01DK111417-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10573471. Licensed CC0.

---

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