# Targeting SWELL1 Signaling to Treat Obesity-Induced Type 2 Diabetes

> **NIH NIH R44** · SENSEION THERAPEUTICS, INC. · 2022 · $990,929

## Abstract

Project Summary/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 β-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.

## Key facts

- **NIH application ID:** 10490426
- **Project number:** 5R44DK121598-03
- **Recipient organization:** SENSEION THERAPEUTICS, INC.
- **Principal Investigator:** Daniel J Lerner
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $990,929
- **Award type:** 5
- **Project period:** 2021-09-17 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490426

## Citation

> US National Institutes of Health, RePORTER application 10490426, Targeting SWELL1 Signaling to Treat Obesity-Induced Type 2 Diabetes (5R44DK121598-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10490426. Licensed CC0.

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