Allosteric modulation of the farnesoid X receptor by a small molecule

被引：14

作者：

Gabler, Matthias ^{[1
]}

Kramer, Jan ^{[1
]}

Schmidt, Jurema ^{[1
]}

Pollinger, Julius ^{[1
]}

Weber, Julia ^{[1
]}

Kaiser, Astrid ^{[1
]}

Loehr, Frank ^{[2
]}

Proschak, Ewgenij ^{[1
]}

Schubert-Zsilavecz, Manfred ^{[1
]}

Merk, Daniel ^{[1
]}

机构：

[1] Goethe Univ Frankfurt, Inst Pharmaceut Chem, Max Von Laue Str 9, D-60438 Frankfurt, Germany

[2] Goethe Univ Frankfurt, Inst Biophys Chem, Max Von Laue Str 9, D-60438 Frankfurt, Germany

来源：

SCIENTIFIC REPORTS | 2018年 / 8卷

关键词：

DRUG DISCOVERY; NUCLEAR RECEPTOR; PROTEIN-KINASE; BILE-ACIDS; IDENTIFICATION; IMATINIB; LIGANDS; POTENT; AMPK; NMR;

D O I：

10.1038/s41598-018-25158-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.

引用

页数：11

共 39 条

[11]

NMR in drug discovery: A practical guide to identification and validation of ligands interacting with biological macromolecules [J].

Gossert, Alvar D. ;

Jahnke, Wolfgang .

PROGRESS IN NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY, 2016, 97 :82-125

[12]

Serine 27, a human Retinoid X Receptor α residue, phosphorylated by protein kinase A is essential for CyclicAMP-mediated downregulation of RXRα function [J].

Harish, S ;

Ashok, MS ;

Khanam, T ;

Rangarajan, PN .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2000, 279 (03) :853-857

[13]

DrugBank screening revealed alitretinoin and bexarotene as liver X receptor modulators [J].

Heitel, Pascal ;

Achenbach, Janosch ;

Moser, Daniel ;

Proschak, Ewgenij ;

Merk, Daniel .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2017, 27 (05) :1193-1198

[14]

Anti-inflammatory and metabolic actions of FXR: Insights into molecular mechanisms [J].

Hollman, Danielle A. A. ;

Milona, Alexandra ;

van Erpecum, Karel J. ;

van Mil, Saskia W. C. .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2012, 1821 (11) :1443-1452

[15]

Identifying Protein Allosteric Transitions for Drug Discovery with 1D NMR [J].

Krimm, Isabelle .

CHEMMEDCHEM, 2017, 12 (12) :901-904

[16]

SAR studies on FXR modulators led to the discovery of the first combined FXR antagonistic/TGR5 agonistic compound [J].

Lamers, Christina ;

Merk, Daniel ;

Gabler, Matthias ;

Flesch, Daniel ;

Kaiser, Astrid ;

Schubert-Zsilavecz, Manfred .

FUTURE MEDICINAL CHEMISTRY, 2016, 8 (02) :133-148

[17]

Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk [J].

Lien, Fleur ;

Berthier, Alexandre ;

Bouchaert, Emmanuel ;

Gheeraert, Celine ;

Alexandre, Jeremy ;

Porez, Geoffrey ;

Prawitt, Janne ;

Dehondt, Helene ;

Ploton, Maheul ;

Colin, Sophie ;

Lucas, Anthony ;

Patrice, Alexandre ;

Pattou, Francois ;

Diemer, Helene ;

Van Dorsselaer, Alain ;

Rachez, Christophe ;

Kamilic, Jelena ;

Groen, Albert K. ;

Staels, Bart ;

Lefebvre, Philippe .

JOURNAL OF CLINICAL INVESTIGATION, 2014, 124 (03) :1037-1051

[18]

Identification of a nuclear receptor for bile acids [J].

Makishima, M ;

Okamoto, AY ;

Repa, JJ ;

Tu, H ;

Learned, RM ;

Luk, A ;

Hull, MV ;

Lustig, KD ;

Mangelsdorf, DJ ;

Shan, B .

SCIENCE, 1999, 284 (5418) :1362-1365

[19]

MATHIS G, 1995, CLIN CHEM, V41, P1391

[20]

Extending the Structure-Activity Relationship of Anthranilic Acid Derivatives As Farnesoid X Receptor Modulators: Development of a Highly Potent Partial Farnesoid X Receptor Agonist [J].

Merk, Daniel ;

Lamers, Christina ;

Ahmad, Khalil ;

Gomez, Roberto Carrasco ;

Schneider, Gisbert ;

Steinhilber, Dieter ;

Schubert-Zsilavecz, Manfred .

JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (19) :8035-8055

← 1 2 3 4 →