# SLC26A3 (DRA) Inhibitors for Treatment of Hyperoxaluria and Nephrolithiasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $310,080

## Abstract

ABSTRACT
Oxalate is an anion with no known biological function in humans. Oxalate is ingested through diet and also
generated by liver as a metabolic waste product. The majority of oxalate (~90%) is excreted by the kidney with
some excretion in stool. In the kidney, oxalate forms poorly soluble calcium oxalate crystals which can lead to
nephrolithiasis, nephrocalcinosis and even chronic kidney disease (CKD). Hyperoxaluria is a major risk factor
for calcium oxalate kidney stones (the most common type constituting 2/3 of all stones), and recently
recognized as a risk factor for CKD progression. Importantly, certain gastrointestinal diseases (bariatric
surgery, inflammatory bowel disease, pancreatic insufficiency) are associated with hyperabsorption of dietary
oxalate in colon, significant hyperoxaluria and urinary stone burden (i.e. enteric hyperoxaluria). Here, we
propose a novel strategy for treatment of hyperoxaluria by blocking oxalate uptake in colon and promoting
stool excretion, which is predicted to reduce urinary oxalate burden and protect kidneys from the detrimental
effects of hyperoxaluria. The target is SLC26A3, an anion (oxalate, Cl-, HCO3-) exchanger highly expressed in
colon facilitating oxalate uptake. SLC26A3 inhibition is a compelling approach for treatment of hyperoxaluria as
suggested by 50-70% lower urine oxalate excretion in knock-out mice and humans with rare SLC26A3
mutations. We recently discovered first-in-class SLC26A3 inhibitors with nanomolar potency and demonstrated
proof-of-concept efficacy of a candidate in mouse models of hyperoxaluria and oxalate nephropathy. SLC26A3
inhibitors will be advanced as first-in-class drugs for hyperoxaluria and calcium oxalate kidney stones.
Recognizing the importance of having back-up candidates, in Aim 1 additional high-throughput screening and
medicinal chemistry will be done to identify novel scaffolds with nanomolar potency and good solubility with
distinct sites of action (intracellular vs. extracellular), metabolic stability and good pharmacokinetics. The
compounds identified and optimized in Aim 1 will be tested in established models of hyperoxaluria and oxalate
nephropathy in mice, as well as in other clinically relevant models of hyperoxaluria including obesity, cystic
fibrosis and bariatric surgery-associated hyperoxaluria, and primary hyperoxaluria. Candidates with good
efficacy in these models will be tested in Aim 3 for in vitro and in vivo toxicity. The goal of these proposed
experiments is to select one or two lead candidate SLC26A3 inhibitors with good animal efficacy and excellent
safety profile for further pre-clinical development.

## Key facts

- **NIH application ID:** 10877183
- **Project number:** 5R01DK126070-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Onur Cil
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $310,080
- **Award type:** 5
- **Project period:** 2020-07-22 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877183

## Citation

> US National Institutes of Health, RePORTER application 10877183, SLC26A3 (DRA) Inhibitors for Treatment of Hyperoxaluria and Nephrolithiasis (5R01DK126070-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10877183. Licensed CC0.

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