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Development and Characterization of Dual‐Site PPARγ Antagonists
Author(s) -
Brust Richard,
Asteian Alice,
Kamenecka Theodore,
Kojetin Douglas
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.630.4
Subject(s) - peroxisome proliferator activated receptor , ligand (biochemistry) , binding site , chemistry , receptor , pharmacology , combinatorial chemistry , biochemistry , biology
Peroxisome proliferator‐activated receptor gamma (PPARγ) has been established as a drug target for type 2 diabetes. Insulin‐sensitizing drugs such as glitazones, which improve plasma glucose maintenance in patients with diabetes, have been shown to target PPARγ. Two commercially available antagonists, T0070907 and GW9662, are used as chemical tools to block ligand binding to PPARγ to show functional specificity of ligands that bind PPARγ. These compounds covalently modify residues Cys285 in the ligand‐binding domain (LBD) of PPARγ. GW9662 and T0070907 share a similar warhead but differ slightly, namely via the presence of a phenyl (GW9662) vs. a pyridyl (T0070907) group. However, in a recent study, we identified a second, alternative ligand‐binding site in PPARγ—one that is not blocked by GW9662 or T0070907. While alternate site ligand binding was not abolished, the phenyl to pyridyl group modification did reduce ligand‐binding affinity to the alternate site, indicating that making further modifications of this scaffold are worth exploring. With this information, we have generated new analogs that target and covalently modify PPARγ. These analogs decrease the binding affinity of PPARγ agonists to the alternate site while also reducing alternate site binding‐induced transactivation in cell based assays. These dual‐site PPARγ antagonists should prove to be a useful chemical tool for the many laboratories that use PPARγ antagonists to demonstrate functional specificity. Support or Funding Information Funding provided by NIH/NIGMS grant R01‐DK101871.