Development of Improved PPAR<i>β</i>/<i>δ</i> Inhibitors

Toth, Philipp M.; Naruhn, Simone; Pape, Veronika F.S.; Dörr, Stefanie; Klebe, G.; Müller, Rolf; Diederich, Wibke E.

doi:10.1002/cmdc.201100408

Cited by 26 publications

(30 citation statements)

References 62 publications

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“…Pharmacokinetic studies have shown that the bioavailability of ST247 is as poor as that of the parent compound (study performed at Cerep, Redmond, WA; data not shown). However, the analysis of further derivatives has provided preliminary evidence that certain positions in the molecule can be modified without a loss of affinity or specificity (Toth et al, 2011). The linkage of suitable side groups to these positions is a potential strategy to improve the bioavailability of ST247 and is currently pursued in our laboratories.…”

Section: Discussionmentioning

confidence: 99%

High-Affinity Peroxisome Proliferator-Activated Receptor β/δ-Specific Ligands with Pure Antagonistic or Inverse Agonistic Properties

Naruhn

Toth²,

Adhikary³

et al. 2011

Mol Pharmacol

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Peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦) is a ligand-regulated nuclear receptor with essential functions in metabolism and inflammation. We have synthesized a new derivative [methyl 3-(N-(4-(hexylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (ST247) structurally related to the published PPAR␤/␦ inhibitory ligand methyl 3-(N-(2-methoxy-4-(phenylamino)phenyl)sulfamoyl)thiophene-2-carboxylate (GSK0660). ST247 has a higher affinity to PPAR␤/␦ than GSK0660, and at equimolar concentrations, it more efficiently 1) induces the interaction with corepressors both in vitro and in vivo, 2) inhibits the agonist-induced transcriptional activity of PPAR␤/␦, and 3) downregulates basal level expression of the peroxisome proliferator responsive element-driven PPAR␤/␦ target gene ANGPTL4. Methyl 3-(N-(4-(tert-butylamino)-2-methoxyphenyl)sulfamoyl)thiophene-2-carboxylate (PT-S58), another high-affinity derivative from our series, also efficiently inhibits agonist-induced transcriptional activation, but in contrast to ST247, it does not enhance the interaction of PPAR␤/␦ with corepressors. PT-S58 rather prevents corepressor recruitment triggered by the inverse agonist ST247. These findings classify ST247 as an inverse agonist, whereas PT-S58 is the first pure PPAR␤/␦ antagonist described to date. It is noteworthy that ST247 and PT-S58 are also effective on PPREindependent functions of PPAR␤/␦: in monocytic cells, both ligands modulate expression of the activation marker CCL2 in the opposite direction as an established PPAR␤/␦ agonist. The possibility to differentially modulate specific functions of PPAR␤/␦ makes these novel compounds invaluable tools to advance our understanding of PPAR␤/␦ biology.

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Section: Discussionmentioning

confidence: 99%

High-Affinity Peroxisome Proliferator-Activated Receptor β/δ-Specific Ligands with Pure Antagonistic or Inverse Agonistic Properties

Naruhn

Toth²,

Adhikary³

et al. 2011

Mol Pharmacol

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“…DG172, its derivatives, and ST247 were synthesized as previously described (Lieber et al, 2012;Toth et al, 2012). GW501516 was purchased from Axxora (Lörrach, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Synthetic antagonistic ligands for PPARb/d have been explored to a much lesser extent, but several inhibitory compounds have been described over the past years. These include the irreversible inhibitor and partial PPARg agonist GSK3787 (Palkar et al, 2010;Shearer et al, 2010), the PPARb/dspecific GSK0660 (Shearer et al, 2008) and its improved derivative methyl 3-{N-[4-(hexylamino)-2-methoxyphenyl]sulfamoyl} thiophene-2-carboxylate (ST247) (Naruhn et al, 2011;Toth et al, 2012), and the stilbene (Z)-2-(2-bromophenyl)-3-{[4-(1-methylpiperazine)amino]phenyl}acrylonitrile (DG172) (Lieber et al, 2012). These ligands act as inverse agonists, as indicated by their inhibitory effect on the basal expression of PPARb/d target genes and an increased recruitment of transcriptional corepressors (Naruhn et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The Inverse Agonist DG172 Triggers a PPARβ/δ-Independent Myeloid Lineage Shift and Promotes GM-CSF/IL-4-Induced Dendritic Cell Differentiation

et al. 2014

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The stilbene derivative (Z)-2-(2-bromophenyl)-3-{[4-(1-methylpiperazine) amino]phenyl}acrylonitrile (DG172) was developed as a highly selective inhibitory peroxisome proliferator-activated receptor (PPAR)b/d ligand. Here, we describe a novel PPARb/d-independent, yet highly specific, effect of DG172 on the differentiation of bone marrow cells (BMCs). DG172 strongly augmented granulocytemacrophage-colony-stimulating factor (GM-CSF)-induced differentiation of primary BMCs from Ppard null mice into two specific populations, characterized as mature (CD11c Ly6B1 cells. In agreement with these findings, transcriptome analyses showed a strong DG172-mediated repression of genes encoding neutrophilic markers in both differentiating wild-type and Ppard null cells, while macrophage/DC marker genes were up-regulated. DG172 also inhibited the expression of transcription factors driving granulocytic differentiation (Cebpe, Gfi1, and Klf5), and increased the levels of transcription factors promoting macrophage/DC differentiation (Irf4, Irf8, Spib, and Spic). DG172 exerted these effects only at an early stage of BMC differentiation induced by GM-CSF, did not affect macrophage-colony-stimulating factortriggered differentiation to macrophages and had no detectable PPARb/d-independent effect on other cell types tested. Structurefunction analyses demonstrated that the 4-methylpiperazine moiety in DG172 is required for its effect on DC differentiation, but is dispensable for PPARb/d binding. Based on these data we developed a new compound, (Z)-2-(4-chlorophenyl)-3-[4-(4-methylpiperazine-1-yl)phenyl]acrylonitrile (DG228), which enhances DC differentiation in the absence of significant PPARb/d binding.

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“…Toward this goal, we made use of recently developed subtype-specific PPARβ/δ inhibitors (ST247, DG172; Figure 1a), which downregulate expression of ANGPTL4 by acting as inverse agonists through an unknown mechanism. 30, 31, 32 Inverse agonists are defined as ligands that, beyond antagonizing agonist binding, exert an opposite effect as an agonist. Thus, in case of PPARβ/δ, an agonist induces a transcriptional activator complex by facilitating the association of PPARβ/δ with coactivators, whereas an inverse agonist triggers the recruitment of transcriptional corepressors and thereby the formation of a repressor complex.…”

Section: Introductionmentioning

confidence: 99%

Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion

et al. 2012

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Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) has a less defined role in tumorigenesis. In the present study, we have identified a function for PPARβ/δ in cancer cell invasion. We show that two structurally divergent inhibitory ligands for PPARβ/δ, the inverse agonists ST247 and DG172, strongly inhibit the serum- and transforming growth factor β (TGFβ)-induced invasion of MDA-MB-231 human breast cancer cells into a three-dimensional matrigel matrix. To elucidate the molecular basis of this finding, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) and microarray analyses, which identified the gene encoding angiopoietin-like 4 (ANGPTL4) as the major transcriptional PPARβ/δ target in MDA-MB-231 cells, previously implicated in TGFβ-mediated tumor progression and metastatic dissemination. We show that the induction of ANGPTL4 by TGFβ and other oncogenic signals is strongly repressed by ST247 and DG172 in a PPARβ/δ-dependent fashion, resulting in the inhibition of ANGPTL4 secretion. This effect is attributable to these ligands' ability to induce a dominant transcriptional repressor complex at the site of transcription initiation that blocks preinitiation complex formation through an histone deacetylase-independent, non-canonical mechanism. Repression of ANGPTL4 transcription by inverse PPARβ/δ agonists is functionally linked to the inhibition of cancer cell invasion into a three-dimensional matrix, as (i) invasion of MDA-MB-231 cells is critically dependent on ANGPTL4 expression, (ii) recombinant ANGPTL4 stimulates invasion, and (iii) reverses the inhibitory effect of ST247 and DG172. These findings indicate that a PPARβ/δ–ANGPTL4 pathway is involved in the regulation of tumor cell invasion and that its pharmacological manipulation by inverse PPARβ/δ agonists is feasible.

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Development of Improved PPARβ/δ Inhibitors

Cited by 26 publications

References 62 publications

High-Affinity Peroxisome Proliferator-Activated Receptor β/δ-Specific Ligands with Pure Antagonistic or Inverse Agonistic Properties

High-Affinity Peroxisome Proliferator-Activated Receptor β/δ-Specific Ligands with Pure Antagonistic or Inverse Agonistic Properties

The Inverse Agonist DG172 Triggers a PPARβ/δ-Independent Myeloid Lineage Shift and Promotes GM-CSF/IL-4-Induced Dendritic Cell Differentiation

Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion

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