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

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