Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment

PPARg 乙酰化抑制剂预防和治疗糖尿病的临床前验证

• 批准号: 10580851
• 负责人: Weidong Wang
• 金额: $ 46.01万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580851
• 关键词: Acetylation; Address; Adipocytes; Adopted; Adverse effects; Affinity; Agonist; Antidiabetic Drugs; Atherosclerosis; Binding; Binding Proteins; Biological Assay; Biological Availability; Biology; Body Weight; Body fat; Cells; Cellular Assay; Chemicals; Clinical; Deacetylase; Deacetylation; Diabetes Mellitus; Diabetes prevention; Drug Kinetics; Drug or chemical Tissue Distribution; Edema; Energy Metabolism; Epidemic; Excretory function; Exhibits; Fluid Balance; Gene Expression; Genes; Genetic; Goals; Half-Life; Heart; Heart Hypertrophy; Heart failure; Hormonal; In Vitro; Insulin; Insulin Resistance; Knock-in Mouse; Lead; Link; Liquid substance; Metabolic; Metabolic Diseases; Metabolism; Mus; Names; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obese Mice; Obesity; PPAR gamma; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Play; Positioning Attribute; Post-Translational Protein Processing; Prevalence; Prevention; Property; Reporting; Research; SIRT1 gene; Safety; Standardization; Structure; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Validation; Water; Weight Gain; Work; absorption; analog; bone; bone loss; clinical development; comorbidity; cost; design; diaries; diet-induced obesity; driving force; drug discovery; efficacy evaluation; glucose tolerance; improved; in vivo; in vivo evaluation; inhibitor; insulin sensitivity; insulin sensitizing drugs; lead candidate; mimetics; mouse model; novel; novel strategies; obesity genetics; pandemic disease; pharmacologic; pre-clinical; prototype; retention rate; side effect; small molecule; systemic toxicity; therapeutic target; therapy development; transcription factor

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.

项目总结