Design and Synthesis of Highly Active Peroxisome Proliferator‐Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity

Toth, Philipp M.; Lieber, Sonja; Scheer, Frithjof; Schumann, Tim; Schober, Yvonne; Nockher, Wolfgang Andreas; Adhikary, Till; Müller‐Brüsselbach, Sabine; Müller, Rolf; Diederich, Wibke E.

doi:10.1002/cmdc.201500594

Cited by 9 publications

(6 citation statements)

References 20 publications

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“…Some of the reported antagonistic ligands display inverse agonism in that they cause the PPAR-mediated transcription to fall below basal levels in a given model system or assay [ 91 , 94 , 95 , 97 , 103 ]. In similarity to other reported PPAR inverse agonists [ 104 – 106 ], the observed subbasal transcription levels are likely reflected in the tendency of such ligands to strengthen the interactions of the PPARs with corepressor proteins, such as NCoR and SMRT, compared to those of the apo-PPARs [ 85 , 88 , 93 , 103 – 106 ].…”

Section: Classical Ppar Agonism Antagonism and Beyondsupporting

confidence: 81%

The PPARΩPocket: Renewed Opportunities for Drug Development

Kaupang

Hansen

2020

PPAR Research

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The past decade of PPARγ research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPARγ ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPARγ ligands, capable of isolating central therapeutic effects of PPARγ modulation, while displaying markedly lower toxicities than previous generations of PPARγ ligands. This review examines the emerging framework around the design of these ligands and seeks to unite its principles with the development of new classes of ligands for PPARα and PPARβ/δ. The focus is on the relationships between the binding modes of ligands, their influence on PPAR posttranslational modifications, and gene expression patterns. Specifically, we encourage the design and study of ligands that primarily bind to the Ω pockets of PPARα and PPARβ/δ. In support of this development, we highlight already reported ligands that if studied in the context of this new framework may further our understanding of the gene programs regulated by PPARα and PPARβ/δ. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.

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Section: Classical Ppar Agonism Antagonism and Beyondsupporting

confidence: 81%

The PPARΩPocket: Renewed Opportunities for Drug Development

Kaupang

Hansen

2020

PPAR Research

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“… 34 , 35 The function of EFABP is to enhance the transcriptional activity of the nuclear receptors PPARβ/δ and promote cell migration, proliferation, and survival. 36 – 38 EFABP is overexpressed in many human cancers, including prostate cancer, 39 , 40 esophageal squamous cell carcinoma, 41 , 42 and breast cancer. 43 , 44 Previous studies have found that EFABP may play an important role in liver cancer.…”

Section: Discussionmentioning

confidence: 99%

Altered epidermal fatty acid-binding protein expression in hepatocellular carcinoma predicts unfavorable outcomes

Lu¹,

Cai²,

Pan³

et al. 2018

CMAR

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ObjectiveHepatocellular carcinoma (HCC) is a rapidly proliferating malignancy that requires large amounts of fatty acids to synthesize cellular membranes and provide energy. Epidermal fatty acid-binding protein (EFABP) is uniquely expressed in epidermal cells, but its role and expression in HCC are not clear.Subjects and methodsA total of 804 HCC specimens were collected to construct a tissue microarray (TMA) and for immunohistochemistry (IHC) analysis. The relationship between EFABP expression and clinical features of patients with HCC was analyzed.ResultsThe EFABP IHC score for HCC tissue was 0.76±0.69, being significantly higher than that for matched nontumorous tissue (0.48±0.55; P<0.001). Using the median IHC score (ie, 0.8) in the tumorous tissue, a high level of EFABP expression was found in 57.3% (461/804) of the cases. Patients with HCC displaying high EFABP expression had poorer tumor differentiation (P=0.029), more vascular invasion (P=0.006), and a higher proportion of late TNM stage disease (P=0.042). Kaplan–Meier analysis revealed that the patients with high EFABP expression had significantly worse outcomes in terms of overall survival (P=0.003), worse disease-free survival (P=0.021), and a higher probability of recurrence (P=0.014). Multivariate analysis indicated that EFABP expression was an independent prognostic variable for overall survival (P=0.021) and disease-free survival (P=0.044). For HCC recurrence, only vascular invasion (P=0.020) and EFABP expression (P=0.026) were independent risk factors.ConclusionOur data revealed that EFABP expression was increased in HCC samples. High EFABP expression was correlated with shorter survival times in patients with HCC and served as an independent factor for worse outcomes. Our study therefore provides a promising bio-marker for the prognostic prediction of HCC and a potential therapeutic target for the disease.

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“…PT-S264 is an inverse PPARβ/δ agonist with improved repressive properties and stability (17). We first tested whether it affects initiation complex formation like the previously used inverse agonist ST247 (36), which reduces RNAPII binding to the ANGPTL4 promoter (4).…”

Section: Pparβ/δ Inverse Agonists Interfere With Formation Of An Initmentioning

confidence: 99%

“…Several fatty acids and their derivatives act as endogenous PPARβ/δ agonists (12,13,14,15). Agonistic ligands cause dissociation of corepressors from the nuclear receptor at ligandregulated target genes, while synthetic inverse agonists recently developed in our group lead to enhanced corepressor recruitment (4,7,16,17). Basal repression of ANGPTL4 and augmented repression in the presence of inverse agonists are largely insensitive to trichostatin A (4), an inhibitor of class I and II HDACs, suggesting an HDAC-independent repression mechanism.…”

Section: Introductionmentioning

confidence: 99%

PPARβ/δ controls Mediator recruitment and transcription initiation

Legrand

Zielke

et al. 2019

Preprint

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In the absence of ligands, the nuclear receptor PPARβ/δ recruits the NCOR and SMRT corepressors, which form complexes with HDAC3, to canonical target genes. Agonistic ligands cause dissociation of corepressors and enable enhanced transcription. Vice versa, synthetic inverse agonists augment corepressor recruitment and repression. Both basal repression of the target gene ANGPTL4 and reinforced repression elicited by inverse agonists are partially insensitive to HDAC inhibition. This raises the question of how PPARβ/δ represses transcription mechanistically. We show that the PPARβ/δ inverse agonist PT-S264 impairs transcription initiation by decreasing recruitment of activating Mediator subunits, RNA polymerase II, and TFIIB, but not of TFIIA, to the ANGPTL4 promoter. Mass spectrometry identifies NCOR as the main PT-S264-dependent interactor of PPARβ/δ.

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Design and Synthesis of Highly Active Peroxisome Proliferator‐Activated Receptor (PPAR) β/δ Inverse Agonists with Prolonged Cellular Activity

Cited by 9 publications

References 20 publications

The PPARΩPocket: Renewed Opportunities for Drug Development

The PPARΩPocket: Renewed Opportunities for Drug Development

Altered epidermal fatty acid-binding protein expression in hepatocellular carcinoma predicts unfavorable outcomes

PPARβ/δ controls Mediator recruitment and transcription initiation

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