# Optimizing SWELL1 modulators to treat non-alcoholic steatohepatitis

> **NIH NIH R44** · SENSEION THERAPEUTICS, INC. · 2020 · $301,025

## Abstract

Non-alcoholic fatty liver (NAFL) and its progression to advanced stage non-alcoholic steatohepatitis (NASH) is
a growing health concern, with 83.1 million Americans affected in 2015, and projections to reach 100.9 million
by 2030. Metabolic syndrome and Type 2 diabetes (T2D) are considered significant pathophysiological
contributors to NAFL-NASH progression, therefore, novel therapeutic strategies to treat T2D and metabolic
syndrome are also expected to benefit NASH, a significant unmet need. We, and others, recently identified a
novel ion channel signaling complex, SWELL1/LRRC8a (Leucine rich repeat containing protein type 8a) that
positively regulates adipocyte insulin-PI3K-AKT2 signaling4, insulin secretion from pancreatic β-cells, and
systemic glucose homeostasis. Moreover, dysfunctional adipocyte SWELL1 predisposes to NAFLD and
hepatocellular carcinoma. 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 pharmacological chaperone to
augment SWELL1 expression and plasma membrane trafficking. In vivo, SN-401 normalizes glucose tolerance
by increasing insulin sensitivity and secretion in obese, T2D mouse models. SN-401 augments glucose uptake
into adipose tissue and myocardium, suppresses hepatic glucose production in KKAy mice, and protects
against hepatic steatosis and hepatocyte ballooning in HFD fed mice. We propose that small molecule
SWELL1 modulators may represent a “first-in-class” therapeutic approach to treat metabolic syndrome
and associated NASH by restoring SWELL1 signaling across multiple organ systems that are
dysfunctional in T2D and contribute to the complex pathophysiology of NASH Our overall objective is to
develop a lead series of SN-401 congeners (SN-40X) from which to select one lead and one back-up compound
to take into humans, with submission of an Investigational New Drug (IND) application to the FDA in Q1 of 2022.
Phase 1 AIMS:
• AIM#1: SAR-directed SN-40X optimization and characterization in vitro to identify preclinical lead
structures.
• AIM#2: Complete in vitro absorption, distribution, metabolism, excretion, toxicity and selectivity
studies.
Phase 2 Aims:
• AIM#1: Perform in vivo oral dosing pharmacokinetics and dose-range finding toxicity studies.
• AIM#2: Perform pre-clinical SN-40X dose-response and head-to-head efficacy studies against
obeticholic acid (OCA) for slowing progression of, halting, or reversing NASH
• AIM#3: Complete solid-state characterization, analytical methods development & validation for lead
and backup chemistry, manufacturing, and controls (CMC) pathways.

## Key facts

- **NIH application ID:** 10081592
- **Project number:** 1R44DK126600-01
- **Recipient organization:** SENSEION THERAPEUTICS, INC.
- **Principal Investigator:** Daniel J Lerner
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $301,025
- **Award type:** 1
- **Project period:** 2020-09-16 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10081592

## Citation

> US National Institutes of Health, RePORTER application 10081592, Optimizing SWELL1 modulators to treat non-alcoholic steatohepatitis (1R44DK126600-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10081592. Licensed CC0.

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