General Information of Drug Therapeutic Target (DTT) (ID: TTS4UGC)

DTT Name Farnesoid X-activated receptor (FXR)
Synonyms Retinoid X receptor-interacting protein 14; RXR-interacting protein 14; RIP14; Nuclear receptor subfamily 1 group H member 4; HRR1; Farnesol receptor HRR-1; FXR; Bile acid receptor; BAR
Gene Name NR1H4
DTT Type
Successful target
[1]
BioChemical Class
Nuclear hormone receptor
UniProt ID
NR1H4_HUMAN
TTD ID
T51426
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MVMQFQGLENPIQISPHCSCTPSGFFMEMMSMKPAKGVLTEQVAGPLGQNLEVEPYSQYS
NVQFPQVQPQISSSSYYSNLGFYPQQPEEWYSPGIYELRRMPAETLYQGETEVAEMPVTK
KPRMGASAGRIKGDELCVVCGDRASGYHYNALTCEGCKGFFRRSITKNAVYKCKNGGNCV
MDMYMRRKCQECRLRKCKEMGMLAECMYTGLLTEIQCKSKRLRKNVKQHADQTVNEDSEG
RDLRQVTSTTKSCREKTELTPDQQTLLHFIMDSYNKQRMPQEITNKILKEEFSAEENFLI
LTEMATNHVQVLVEFTKKLPGFQTLDHEDQIALLKGSAVEAMFLRSAEIFNKKLPSGHSD
LLEERIRNSGISDEYITPMFSFYKSIGELKMTQEEYALLTAIVILSPDRQYIKDREAVEK
LQEPLLDVLQKLCKIHQPENPQHFACLLGRLTELRTFNHHHAEMLMSWRVNDHKFTPLLC
EIWDVQ
Function
Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response. The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression. The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA. Modulates lipid homeostasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly. Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element. Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance. Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells. Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2. Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays an anti-inflammatory role in liver inflammation; proposed to inhibit proinflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity).
KEGG Pathway
Bile secretion (hsa04976 )
Reactome Pathway
PPARA activates gene expression (R-HSA-1989781 )
Endogenous sterols (R-HSA-211976 )
Recycling of bile acids and salts (R-HSA-159418 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
3 Approved Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Chenodiol DMQ8JIK Cholelithiasis DC11 Approved [2]
Guggulsterone DMP7LK1 Osteoarthritis FA00-FA05 Approved [1]
obeticholic acid DM3Q1SM Primary biliary cholangitis DB96.1 Approved [3]
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10 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
GS-9674 DM936V7 Primary sclerosing cholangitis DB96.2 Phase 3 [4]
Apomine DM6B9HP Osteopetrosis LD24.10 Phase 2 [5]
EDP-305 DMGJYZ8 Non-alcoholic steatohepatitis DB92.1 Phase 2 [6]
EYP001 DM5PBLM Non-alcoholic steatohepatitis DB92.1 Phase 2 [7]
LJN452 DM3XRUH Primary biliary cholangitis DB96.1 Phase 2 [8]
LMB763 DMQOXNL Diabetic nephropathy GB61.Z Phase 2 [9]
MET409 DM89QXT Non-alcoholic steatohepatitis DB92.1 Phase 2 [10]
AGN-242266 DMVHPOX Non-alcoholic steatohepatitis DB92.1 Phase 1 [11]
PX-102 DMWU682 Hepatic fibrosis DB93.0 Phase 1 [12]
Turofexorate isopropyl DM36ONA Hyperlipidaemia 5C80 Phase 1 [13]
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⏷ Show the Full List of 10 Clinical Trial Drug(s)
45 Patented Agent(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
PMID29649907-Compound-1 DMDKT9X N. A. N. A. Patented [14]
PMID29649907-Compound-10 DMNE9AX N. A. N. A. Patented [14]
PMID29649907-Compound-11 DMSC9MH N. A. N. A. Patented [14]
PMID29649907-Compound-12 DMBHT2E N. A. N. A. Patented [14]
PMID29649907-Compound-13 DMLBQUS N. A. N. A. Patented [14]
PMID29649907-Compound-14 DMQAV30 N. A. N. A. Patented [14]
PMID29649907-Compound-15 DMMIKFU N. A. N. A. Patented [14]
PMID29649907-Compound-18 DMBVOZK N. A. N. A. Patented [14]
PMID29649907-Compound-19 DMFL38V N. A. N. A. Patented [14]
PMID29649907-Compound-2 DMM4TBH N. A. N. A. Patented [14]
PMID29649907-Compound-20 DMGNW34 N. A. N. A. Patented [14]
PMID29649907-Compound-21 DMES0UY N. A. N. A. Patented [14]
PMID29649907-Compound-22 DMXW108 N. A. N. A. Patented [14]
PMID29649907-Compound-23 DMW7T45 N. A. N. A. Patented [14]
PMID29649907-Compound-24 DMUHNS7 N. A. N. A. Patented [14]
PMID29649907-Compound-25 DMALOEW N. A. N. A. Patented [14]
PMID29649907-Compound-26 DM6O78C N. A. N. A. Patented [14]
PMID29649907-Compound-27 DMQDGZL N. A. N. A. Patented [14]
PMID29649907-Compound-28 DMYMKZC N. A. N. A. Patented [14]
PMID29649907-Compound-29 DMEVZIK N. A. N. A. Patented [14]
PMID29649907-Compound-3 DMPVSG9 N. A. N. A. Patented [14]
PMID29649907-Compound-30 DM0SY7Q N. A. N. A. Patented [14]
PMID29649907-Compound-31 DME6H8Q N. A. N. A. Patented [14]
PMID29649907-Compound-32 DM7E9HA N. A. N. A. Patented [14]
PMID29649907-Compound-33 DM39HCU N. A. N. A. Patented [14]
PMID29649907-Compound-34 DMUDKE0 N. A. N. A. Patented [14]
PMID29649907-Compound-35 DMSWJPO N. A. N. A. Patented [14]
PMID29649907-Compound-36 DMP5KEW N. A. N. A. Patented [14]
PMID29649907-Compound-37 DM8WKYT N. A. N. A. Patented [14]
PMID29649907-Compound-38 DMMP09F N. A. N. A. Patented [14]
PMID29649907-Compound-39 DMI3ELU N. A. N. A. Patented [14]
PMID29649907-Compound-4 DMO45VP N. A. N. A. Patented [14]
PMID29649907-Compound-40 DMS6UD2 N. A. N. A. Patented [14]
PMID29649907-Compound-41 DM26IRH N. A. N. A. Patented [14]
PMID29649907-Compound-42 DMSAD9B N. A. N. A. Patented [14]
PMID29649907-Compound-44 DMBA2S3 N. A. N. A. Patented [14]
PMID29649907-Compound-5 DMDWSIE N. A. N. A. Patented [14]
PMID29649907-Compound-8 DMV2D5M N. A. N. A. Patented [14]
PMID29649907-Compound-9 DMA6H4W N. A. N. A. Patented [14]
PMID29649907-Compound-INT767 DMA0RI8 N. A. N. A. Patented [14]
PMID30259754-Compound-INT-767 DME0RJ2 N. A. N. A. Patented [8]
PMID30259754-Compound-LY2562175 DMZ5CDY N. A. N. A. Patented [8]
PMID30259754-Compound-Px-102 DM78IN5 N. A. N. A. Patented [8]
PMID30259754-Compound-pyrrole[2,3-d]azepines DMVP16K N. A. N. A. Patented [8]
PMID30259754-Compound-WAY-362450 DMDKSJQ N. A. N. A. Patented [8]
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⏷ Show the Full List of 45 Patented Agent(s)
2 Discontinued Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
SB-756050 DMXFQS1 Type-2 diabetes 5A11 Discontinued in Phase 2 [15]
SKF-97426 DM40HTZ Hyperlipidaemia 5C80 Discontinued in Phase 2 [16]
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1 Preclinical Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
INT-767 DMRJ9P4 Hepatic fibrosis DB93.0 Preclinical [17]
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8 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
1,1-bisphosphonate esters DMG362U Discovery agent N.A. Investigative [5]
12-O-deacetyl-12-epi-19-deoxy-21-hydroxyscalarin DMKH0OC Discovery agent N.A. Investigative [18]
22R-hydroxycholesterol DME8273 Discovery agent N.A. Investigative [19]
AGN-34 DM5ECDM Discovery agent N.A. Investigative [20]
cholesten DMKM3WJ Discovery agent N.A. Investigative [21]
desmosterol DMV8SUM Discovery agent N.A. Investigative [21]
Fexaramine DMWCLQ5 Discovery agent N.A. Investigative [22]
GW4065 DMFRP7H Discovery agent N.A. Investigative [2]
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⏷ Show the Full List of 8 Investigative Drug(s)

Molecular Expression Atlas (MEA) of This DTT

Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This DTT
Disease Name ICD 11 Studied Tissue p-value Fold-Change Z-score
Osteoarthritis FA20 Synovial tissue 2.77E-01 -0.08 -0.4
Type 2 diabetes 5A11 Liver tissue 5.72E-01 0.39 1.68
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References

1 Effect of guggulsterone and cembranoids of Commiphora mukul on pancreatic phospholipase A(2): role in hypocholesterolemia. J Nat Prod. 2009 Jan;72(1):24-8.
2 Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J Biol Chem. 2002 Aug 30;277(35):31441-7.
3 2016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76.
4 The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. Hepatology. 2019 Sep;70(3):788-801.
5 The nuclear receptors FXR and LXRalpha: potential targets for the development of drugs affecting lipid metabolism and neoplastic diseases. Curr Pharm Des. 2001 Mar;7(4):231-59.
6 A novel non-bile acid FXR agonist EDP-305 potently suppresses liver injury and fibrosis without worsening of ductular reaction. Liver Int. 2020 Jul;40(7):1655-1669.
7 Clinical pipeline report, company report or official report of ENYO Pharma.
8 FXR modulators for enterohepatic and metabolic diseases.Expert Opin Ther Pat. 2018 Nov;28(11):765-782.
9 Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis. J Med Chem. 2020 Apr 23;63(8):3868-3880.
10 Clinical pipeline report, company report or official report of Metacrine.
11 Clinical pipeline report, company report or official report of AbbVie.
12 An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers. Gastroenterology. 2018 Oct;155(4):1012-1016.
13 A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am J Physiol Gastrointest Liver Physiol. 2009 Mar;296(3):G543-52.
14 Farnesoid X receptor modulators 2014-present: a patent review.Expert Opin Ther Pat. 2018 May;28(5):351-364.
15 Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
16 SK&F 97426-A a more potent bile acid sequestrant and hypocholesterolaemic agent than cholestyramine in the hamster. Atherosclerosis. 1993 Jun;101(1):51-60.
17 FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity. J Am Soc Nephrol. 2018 Jan;29(1):118-137.
18 Scalarane sesterterpenes from a marine sponge of the genus Spongia and their FXR antagonistic activity. J Nat Prod. 2007 Nov;70(11):1691-5.
19 Oxysterol 22(R)-hydroxycholesterol induces the expression of the bile salt export pump through nuclear receptor farsenoid X receptor but not liver ... J Pharmacol Exp Ther. 2006 Apr;317(1):317-25.
20 Farnesoid X receptor: from structure to potential clinical applications. J Med Chem. 2005 Aug 25;48(17):5383-403.
21 Identification of farnesoid X receptor beta as a novel mammalian nuclear receptor sensing lanosterol. Mol Cell Biol. 2003 Feb;23(3):864-72.
22 How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.