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Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment

Award Number: R01DK128848
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment - 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 insulin resistance and T2D.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $439,260 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/11/2024	NON-COMPETING CONTINUATION	$411,806
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	5/2/2024	NON-COMPETING CONTINUATION	$27,454
2024	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $439,260

Issue Date FY: 2023 ( Subtotal = $460,068 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/23/2023	NON-COMPETING CONTINUATION	$460,068
														Subtotal = $460,068

Issue Date FY: 2022 ( Subtotal = $462,522 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/24/2022	NON-COMPETING CONTINUATION	$46,257
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/28/2022	NON-COMPETING CONTINUATION	$416,265
														Subtotal = $462,522

Issue Date FY: 2021 ( Subtotal = $476,180 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/15/2021	NEW	$476,180
														Subtotal = $476,180

Grand Total All Awards = $1,838,030

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Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment

Award Number: R01DK128848

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/15/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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