# Inhibition of hepatic (V)LDL production by a novel antagonist of carboxyl esterase 1

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $512,957

## Abstract

Project Summary
We used a human iPSC-derived hepatocyte platform to identify a family of structurally related
small molecules that can reduce the production of APOB by the liver. These small molecules
are highly effective, do not cause abnormal lipid accumulation, and have a chemical structure
that is distinct from any known cholesterol lowering drug. Such compounds have the potential to
treat hypercholesterolemia and steatosis. In the current application we propose to define the
molecular mechanisms through which the compounds act. In preliminary data we show that the
compounds inhibit human carboxylesterase 1 (CES1). In the three proposed aims we will i)
identify the binding characteristics of the compounds to CES1 and define their specificity using
crystallography and biochemical assays, ii) use iPSC-hepatocytes to definitively establish the
role of CES1 in mediating (V)LDL-cholesterol production by the compounds, and iii) determine
the efficacy of the compounds in lowering cholesterol and steatosis humanized mouse models.

## Key facts

- **NIH application ID:** 10913480
- **Project number:** 5R01DK136328-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** STEPHEN A DUNCAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $512,957
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913480

## Citation

> US National Institutes of Health, RePORTER application 10913480, Inhibition of hepatic (V)LDL production by a novel antagonist of carboxyl esterase 1 (5R01DK136328-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10913480. Licensed CC0.

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