# Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2021 · $476,180

## Abstract

PROJECT SUMMARY
This proposal aims to leverage basic discoveries in interdisciplinary fields to develop a novel and safer therapy
for pandemic type 2 diabetes (T2D). Obesity-linked insulin resistance is the key driving force for T2D and other
metabolic disorders. Despite the wide use of commonly used anti-diabetic drugs for T2D treatment, the
prevalence of T2D continues to soar with an annual cost over $300 billion in the US. The transcription factor
peroxisome proliferator-activated receptor γ (PPARγ) is an important therapeutic target for insulin
sensitization and its full agonist TZD drugs are by far the most potent insulin-sensitizing drugs. However, TZD
drugs are associated with adverse side effects including heart failure and weight gain, as TZD-induced full
agonism of PPARγ activates not only the expression of genes responsible for insulin sensitizing but also of
those genes associated with side effects, thereby severely hampering the clinical use of TZDs. Recent studies
have indicated that PPARγ posttranslational modifications (PTMs) may lead to the selective activation of
PPARγ target genes that results in the decoupling of the beneficial effects on insulin sensitizing from the TZD-
related adverse effects. Our team recently discovered that deacetylation at K268 and K293 in PPARγ by the
NAD+-dependent deacetylase SirT1 plays a key role in such decoupling. Excitingly, the PIs have developed a
novel class of PPARγ agonist, TPMD, that bound to PPARγ to specifically inhibit PPAR acetylation. Importantly,
TPMD improved insulin sensitivity and increased white-to-brown adipocyte conversion (browning) and energy
expenditure without causing TZD-associated side effects in both genetic and diary obesity mouse models. In this
application, the team led by the two PIs with complementary expertise in diabetes drug discovery and PPARγ
biology will use TPMD as the starting molecule to identify the first-in-class inhibitor of PPARγ acetylation that
exert potent insulin-sensitizing and browning activities and better safety and pharmacokinetic (PK) properties.
In Aim 1, they will employ structure-based design through iterative and parallel medicinal chemistry to identify
TPMD analogs with improved potency of inhibiting PPARγ acetylation. In Aim 2, the lead analogs will be
proceeded to the standardized core in vitro ADMET assays and in vivo pharmacokinetics studies to select those
with the most favorable pharmacological properties. In Aim 3, the lead candidates will be tested rigorously for
their in vivo efficacy and safety in obesity and genetic mouse models. The PIs will adopt their “standardized”
metabolic characterizations and assessments of TZD-associated adverse side effects. The proposed studies will
produce first-in-class PPARγ acetylation inhibitors that have improved insulin-sensitizing potency, safety, and
PK profiles. Thus, completion of this research will be well-poised for further clinical development to curtail the
current epidemics of insuli...

## Key facts

- **NIH application ID:** 10225150
- **Project number:** 1R01DK128848-01
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Li Qiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $476,180
- **Award type:** 1
- **Project period:** 2021-06-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225150

## Citation

> US National Institutes of Health, RePORTER application 10225150, Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment (1R01DK128848-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10225150. Licensed CC0.

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