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Targeting SWELL1 Signaling to Treat Obesity-Induced Type 2 Diabetes

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44DK121598-02A1
Agency Tracking Number: R44DK121598
Amount: $1,984,107.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: 200
Solicitation Number: PA20-260
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-09-17
Award End Date (Contract End Date): 2023-07-31
Small Business Information
Saint Louis, MO 63105-2116
United States
DUNS: 117329601
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (415) 637-1636
Business Contact
Phone: (415) 637-1636
Research Institution

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
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.

* Information listed above is at the time of submission. *

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