FK614, a Novel Peroxisome Proliferator-Activated Receptor γ Modulator, Induces Differential Transactivation Through a Unique Ligand-Specific Interaction With Transcriptional Coactivators

Abstract

Abstract. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcriptional factor implicated in regulating adipogenesis, glucose homeostasis, and in mediating the action of the insulin sensitizing anti-diabetic thiazolidinedione (TZD) compounds. [3-(2,4-Dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3-H-benzimidazole-5-carboxamide] (FK614) is a structurally novel PPARγ agonist that demonstrates potent anti-diabetic activity in vivo. Herein, we describe that FK614 is a selective PPARγ ligand with specific transactivation properties that are dependent upon the context of coactivators. FK614 dissociates the corepressors NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors) from PPARγ as effectively as rosiglitazone and pioglitazone, but can also differentially induce a ligand specific interaction of PPARγ with coactivators. The amount of CBP (CREBbinding protein) and SRC-1 (steroid receptor coactivator-1) recruited by FK614 was less than that induced by rosiglitazone and pioglitazone, but FK614 caused similar PGC-1α (PPARγ coactivator-1α) recruitment as these compounds. As a consequence of these ligand-specific differences in the strength of ligand-type specific interactions of PPARγ and coactivators, FK614 functions as a partial or full agonist for transcriptional activation depending upon the amount of specific coactivators in cells following overexpression. In conclusion, FK614 is a novel, non-TZD type, and selective PPARγ modulator whose pharmacological properties are distinct from rosiglitazone and pioglitazone.

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

“…This differential result could be due to the conformational changes of the PPARc LBD induced by ligands unveiling a dynamic response of the receptor. Finally, recent studies have shown that, upon binding of specific ligands, the interactions between PPARc and coregulators often depend on their amount present in a given cell, explaining why a ligand can function as a partial or full agonist [59][60][61]. On the basis of these considerations, it is tempting to speculate that the differential binding of cladosporol A and B (more specifically, 2A and 2B) to PPARc may influence the choice of coregulators through conformational changes induced onto the LBD that may account for the different pathways they regulate.…”

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…A conceptual model of PPARg function is emerging that offers some insight into how SPPARgMs may tune PPARg to produce selective effects . The binding of a particular ligand (or no ligand) by PPARg produces a unique equlibria of conformations and dynamics that favors/disfavors interaction with a particular set of protein kinases, ubiquitin ligases, or coregulators, thus producing ligand-specific transcriptional effects (Oberfield et al, 1999;Rocchi et al, 2001;Fujimura et al, 2005;Pascual et al, 2005;Burgermeister et al, 2006;Kim et al, 2006c;Motani et al, 2009;Choi et al, 2010). Many of the SPPARgMs do show distinct cofactor binding from rosiglitazone or pioglitazone; however, the right combination of coregulator recruitment necessary for desired physical effects remains unclear.…”

A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression

“…Indeed, our observation that substitution of the AP-1 binding site only partially impaired the inhibitory effect is consistent with the notion that MPBD targets multiple cis elements. Therefore, our finding that MPBD inhibits MMP-9 expression by antagonizing the AP-1 function adds a new function to the benzimidazole family of compounds that also inhibit the activity of casein kinase II, topoisomerase I, or peroxisome proliferator-activated receptor-␥ at a concentration range similar to MPBD (Rangarajan et al, 2000;Fujimura et al, 2005;Tapia et al, 2006).…”