Targeting SWELL1 signaling to treat obesity-induced type 2 diabetes
Ended Project Grant Awarded Last action
- Award ID
- R44DK121598
- Recipient
-
Senseion Therapeutics Inc. UEI V2KQH21BGKY5
- Awarding agency
-
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,981,858
Award facts
- Assistance listing
- 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
- Completion date
- Originally
- Place of performance
- Missouri, USA
Award details come from USAspending.gov.
Description
- Abstract
- More than 100 million americans currently have diabetes or pre-diabetes, a condition that can lead to type 2 diabetes (T2D) within five years, and that vastly increases adverse cardiovascular events. T2D is characterized by both a loss of insulin sensitivity of target tissues (FAT, skeletal muscle, liver) and ultimately, impaired insulin secretion from the pancreatic b-cell. We, and others, recently identified a novel ION channel signaling complex, SWELL1/LRRC8A (leucine-rich repeat containing protein type 8A) that positively regulates insulin-mediated intracellular signaling in adipose, skeletal muscle, and endothelium, insulin secretion from pancreatic SS-cells, and systemic glucose homeostasis. We have identified a small molecule modulator, dcpib (renamed SN- 401), as a tool compound that binds the SWELL1-LRRC8 complex and functions as a molecular chaperone to augment SWELL1 expression and plasma membrane trafficking. In vivo, SN-401 normalizes glucose tolerance by increasing insulin sensitivity and secretion T2D mouse models. SN-401 augments glucose uptake into adipose tissue and myocardium, suppresses hepatic glucose production, and protects against hepatic steatosis and hepatocyte damage. Combining cryo-EM with molecular docking simulations, and functional studies we have validated a structure-activity relationship (SAR) to generate novel SN-401 congeners with in vivo anti-hyperglycemic activity in T2D models (SN-40X). We propose that small molecule SWELL1 modulators may represent a first-in-class therapeutic approach to treat T2D and associated cardiovascular disease by restoring SWELL1 signaling across multiple organ systems that are dysfunctional in T2D. Our overall objective is to develop a lead series of SN-401 congeners (SN-40X) from which to select one lead compound and one back-up to take into humans, with submission of an investigational new drug (IND) application to the FDA in Q1 of 2023. Aim 1: SAR-directed SN-40X optimization and characterization in vitro to refine preclinical lead structures. Aim 2: perform in vivo dose-range finding toxicity studies, pre-clinical SN-40X dose-response and head-to-head efficacy studies against SGLT2I, empagliflozin and GLP1A, liraglutide aim 3: manufacture the lead SN-40X compound under cgmp conditions required for all IND-enabling and 24-month stability studies and some phase i clinical studies.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $990,929 | |
| Amendment | $990,929 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Original award | $0 |
Quick answers
Who received award R44DK121598?
R44DK121598 was awarded to Senseion Therapeutics Inc. by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on September 17, 2021.
How much is award R44DK121598 worth?
$1,981,858 has been obligated on R44DK121598.
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