Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ

Abstract

Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.

Study on Drug‐Drug Interactions Between Chiglitazar, a Novel PPAR Pan‐Agonist, and Metformin Hydrochloride in Healthy Subjects

“…Regarding PPAR‐δ, as yet there has been no drug approved in clinical practice, although animal experiments indicated that PPAR‐δ could raise the HDL‐C level without influencing the levels of TG, very‐low‐density lipoprotein, or low‐density lipoprotein cholesterol, and it might be involved in inhibition of inflammation . According to their mutually compensatory and sometimes antagonistic effects, a less potent and well‐balanced agonist targeting all 3 PPAR types may provide more comprehensive efficacy in T2DM treatment, which is to increase insulin sensitivity, regulate blood glucose, and minimize the side effects of metabolic dysfunction, cardiovascular disease, weight gain, and bone fracture, building up a brand‐new T2DM therapy …”

“…Chiglitazar (CHI), a novel configuration‐restricted non‐TZD PPAR pan‐agonist, is currently in its phase 3 clinical development for treatment of patients with T2DM in China (http://www.chinadrugtrials.org.cn/, with registration number CTR20131996; https://clinicaltrials.gov, with registration identifier number NCT02121717). Previous studies, both in vitro and in vivo, demonstrated that CHI had moderate transcription activity in PPAR‐α, PPAR‐γ, and PPAR–δ types . It could upregulate the expression of genes like ANGPTL4 and PDK4 , which are involved in glucose and lipid metabolism.…”

“…8 According to their mutually compensatory and sometimes antagonistic effects, a less potent and well-balanced agonist targeting all 3 PPAR types may provide more comprehensive efficacy in T2DM treatment, which is to increase insulin sensitivity, regulate blood glucose, and minimize the side effects of metabolic dysfunction, cardiovascular disease, weight gain, and bone fracture, building up a brand-new T2DM therapy. [9][10][11] Chiglitazar (CHI), a novel configuration-restricted non-TZD PPAR pan-agonist, is currently in its phase 3 clinical development for treatment of patients with T2DM in China 10 (http://www.chinadrugtrials.org.cn/, with registration number CTR20131996; https:// clinicaltrials.gov, with registration identifier number NCT02121717). Previous studies, both in vitro and in vivo, demonstrated that CHI had moderate transcription activity in PPAR-α, PPAR-γ , and PPAR-δ types.…”

“…Previous studies, both in vitro and in vivo, demonstrated that CHI had moderate transcription activity in PPAR-α, PPAR-γ , and PPAR-δ types. 11,12 It could upregulate the expression of genes like ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. And the early phase of the clinical trial of CHI evidenced its effectiveness in ameliorating glycometabolism.…”

To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations

“…TZDs act as insulin sensitizers that improve glycemic control but have now become "Nonformulary oral options that are nonpreferred but can be considered in patients at high hypoglycemia risk where cost is an issue" because studies have linked these drugs to hepatotoxicity, increased risk for cardiovascular failure, myocardial infarction, increased risk for bladder cancer, and body weight gain [6,[25][26][27][28][29][30][31][32]. Despite the adverse effects of current medications, development of new PPAR agonists are still of great interest because of the unique and promising feature of this class of drug, including the ability to directly target insulin resistance and provide a more durable glycemic (HbA1c) control when compared to other antidiabetic medications [33]. In an attempt to reduce the reverse effects, alternative approaches were considered to target the PPAR receptors including partial PPARγ agonists [34][35][36][37][38][39][40][41][42][43][44], multitargeted cooperative PPARα/γ dual agonists [28,31,40,[45][46][47][48][49][50][51][52][53][54][55][56][57][58], and PPARα/β/γ pan-agonists [30,35,[59]…”