# The Development of TGR5 Antagonists for the Treatment of Cholangiopathies

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $496,591

## Abstract

PROJECT SUMMARY
The objective of this proposal is to develop antagonists of the bile acid receptor TGR5 as a potential treatment
for polycystic liver disease (PLD), a genetic cholangiopathy characterized by hepatic cystogenesis.
Cholangiopathies are a group of liver diseases in which cholangiocytes, the epithelial cells lining intrahepatic bile
ducts, are the primary target. PLD, is incurable and exists as isolated Autosomal Dominant PLD or co-exists with
Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive PKD. Despite recent
advances in the pathogenesis of PLD, there are no therapies for these devastating conditions. Our previous work
implicated cAMP (increased in cystic cholangiocytes) as an important central component in the network of
dysregulated signaling pathways in PLD and led us to cAMP-targeted strategies for disease treatment. We
discovered TGR5, a G protein-coupled bile acid receptor (GPCR) linked to cAMP signaling, plays an important
role in cAMP-driven hepatic cystogenesis in PLD. We demonstrated that TGR5 is overexpressed in cystic
cholangiocytes in vitro and in vivo, and found TGR5 agonists increase intracellular cAMP, triggering
cholangiocyte hyper-proliferation and enhancing cyst growth both in vitro and in PCK rats (worsening disease
progression). Further findings support TGR5's role in the pathogenesis of hepatic cystogenesis. Thus, our
objective is to develop antagonists to inhibit TGR5 activity, thus reducing hepatic cystogenesis in PLD. As no
selective small molecule TGR5 antagonists have been reported, we completed an HTS identifying several
promising leads including SBI-319. We propose this lead optimization campaign to develop orally available
compounds for in vivo testing to validate TGR5 as a potential target for PLD.
Central Hypothesis. Selective TGR5 antagonists will inhibit cAMP levels in cystic cholangiocytes, thus reducing
cAMP-driven cell proliferation and hepatic cystogenesis, yielding a novel therapeutic target for PLD. To explore
our central hypothesis, we will perform the following specific aims: Aim 1. To design and synthesize TGR5
antagonists orally active in vivo. Through iterative cycles of chemistry, we will identify compounds suitable for
in vivo efficacy studies. Aim 2. To clarify the mechanisms of action of SBI-319 analogs in PLD. We will 1)
assess SBI-319 analog effects on: (i) cAMP production in cystic cholangiocytes; (ii) cholangiocyte proliferation;
and (iii) growth of hepatic cystic structures in 3D cultures; 2) examine the expression of TGR5 and Gαs proteins,
and their coupling upon treatment with SBI-319. Aim 3. To evaluate the efficacy of TGR5 antagonists as a
treatment for PLD. We will assess effects of SBI-319 analogs on hepatic and renal cystogenesis and clarify the
role of TGR5 inhibition in disease progression in vivo.
In addition to PLD as a potential therapeutic application, findings show TGR5 is over-expressed in
cholangiocarcinoma and is up-regulated in non-bi...

## Key facts

- **NIH application ID:** 10018484
- **Project number:** 5R01DK117133-02
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Nicholas F. LaRusso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $496,591
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018484

## Citation

> US National Institutes of Health, RePORTER application 10018484, The Development of TGR5 Antagonists for the Treatment of Cholangiopathies (5R01DK117133-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10018484. Licensed CC0.

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