# Small molecules targeting hepatic glucose production and insulin resistance

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2020 · $656,218

## Abstract

Abstract
Type 2 diabetes (T2D), particularly associated with obesity, is an epidemic in the US and worldwide and it is
the leading cause of renal diseases, non-traumatic loss of limb and blindness. Despite the fact that there are
current antidiabetic drugs, such as insulin secretagogues and metformin, used in the treatment of T2D, there is
an urgent medical need of additional targeted therapies for an improved management of this disease in
patients in which these current drugs have moderate efficacy. As T2D progresses, there is exacerbated and
uncontrolled hepatic glucose production that strongly contributes to chronic hyperglycemia, a major cause of
the various diabetic pathologies. Acetylation of the transcriptional coactivator PGC-1α selectively suppresses
hepatic glucose production and ameliorates T2D. We have used a series of chemical high throughput and
secondary assays to identify a small molecule, SR-18292, that increases PGC-1α acetylation, suppressing its
gluconeogenic activity. SR-18292 inhibits glucagon and PGC-1α-dependent gluconeogenic gene expression
through increased binding between PGC-1α and the GCN5 Acetyl Transferase, displacing the transcription
factor HNF4α from gluconeogenic promoters and reducing epigenetic histone activation marks. In diabetic
mice, SR-18292 decreases hepatic glucose output, hyperglycemia and increases liver insulin sensitivity.
Combined, these studies support targeting this pathway for potential therapeutic intervention for T2D. Thus,
the primary goal of this application is to characterize SR-18292 and optimize analogs that could have the
potential to become a new anti-diabetic drug therapy in T2D. We will perform a complete SAR (structure and
activity relationship), DMPK (drug metabolism and pharmacokinetics), toxicity and a series of in vitro and in
vivo metabolic studies to validate the pathway and to identify a SR-18292 analog with robust anti-diabetic
activities. The experimental design is focused on two aims: 1) SAR and DMPK studies based on the SR-18292
molecule scaffold using in-vitro and in-vivo assays and target identification (Specific Aim 1) and, 2) toxicology
and in-vivo metabolic studies using the SR-18292 analog (Specific Aim 2). The outcomes of this proposal will
provide significant contribution to the early-stage preclinical validation for the SR-18292 analogs as therapeutic
leads for management of T2D and insulin resistance.

## Key facts

- **NIH application ID:** 9899246
- **Project number:** 5R01DK117655-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Patrick Robert Griffin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $656,218
- **Award type:** 5
- **Project period:** 2019-03-21 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899246

## Citation

> US National Institutes of Health, RePORTER application 9899246, Small molecules targeting hepatic glucose production and insulin resistance (5R01DK117655-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9899246. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*