# Optimizing small molecule SWELL1-LRRC8 modulators to treat Type 2 diabetes

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $423,936

## Abstract

Project Summary/Abstract
Type 2 diabetes (T2D) is characterized by both a loss of insulin sensitivity of target and ultimately, impaired
insulin secretion from the pancreatic b-cell. We have identified a novel SWELL1-mediated signaling pathway
that regulates both insulin sensitivity and insulin secretion, whereby SWELL1 loss-of-function can both down-
regulate insulin signaling in target tissues, and insulin secretion from the pancreatic b-cell. 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, plasma membrane trafficking
and signaling. In vivo, SN-401 normalizes glucose tolerance by increasing insulin sensitivity and secretion in
murine T2D models. SN-401 also augments glucose uptake into adipose tissue and myocardium, suppresses
hepatic glucose production in KKAy mice, and protects against hepatic steatosis in HFD fed mice.
We propose that small molecule SWELL1 modulators represent a “first-in-class” therapeutic approach
to treat metabolic syndrome and associated diseases by restoring SWELL1 signaling across multiple
organ system that are dysfunctional in T2D. Combining recent cryo-EM data of SN-401 bound to its target
SWELL1/LRRC8a with molecular docking simulations we have validated a structure-activity relationship (SAR)
based approach to generate novel SN-401 congeners with either enhanced or reduced on-target activity. The
objectives are: 1. To establish the optimal dosing regimen and mode of administration for the newly synthesized,
SAR-inspired SN-401 congeners synthesized to date to achieve a therapeutic effect for T2D; 2. To evaluate for
putative beneficial cardiovascular effects; 3. To determine the primary tissue-site(s) of action of SN-401 in vivo;
4. SAR-based compound synthesis to refine and optimize the leads based on in vitro ADMET and selectivity
screens, and efficacy studies in vivo. We propose the following specific AIMs
AIM#1: Determine optimal dosing regimen, therapeutic effect and target tissue(s) of novel SAR-inspired
SN-401 congeners.
AIM#2: SAR-directed SN-401 optimization and characterization in vitro and in vivo to identify preclinical
lead structures.
This proposal seeks to use a validated chemical biology approach to expand a pipeline of novel,
bioactive pharmacological SWELL1 signaling modulators for the treatment of T2D, metabolic syndrome
and associated diseases to ultimately take into man in the form of a clinical trial for efficacy in humans.

## Key facts

- **NIH application ID:** 10216501
- **Project number:** 1R01DK126068-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Rajan Sah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,936
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216501

## Citation

> US National Institutes of Health, RePORTER application 10216501, Optimizing small molecule SWELL1-LRRC8 modulators to treat Type 2 diabetes (1R01DK126068-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10216501. Licensed CC0.

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