Details of the Drug Therapeutic Target (DTT)

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]
• Related Disease:
  Autoimmune liver disease [ICD-11: DB96]
  Cholelithiasis [ICD-11: DC11]
  Osteoarthritis [ICD-11: FA00-FA05]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: NR1H4_HUMAN
• TTD ID: T51426
• 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).
• 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

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Chenodiol	DMQ8JIK	Cholelithiasis	DC11	Approved	[2], [3]
Guggulsterone	DMP7LK1	Osteoarthritis	FA00-FA05	Approved	[1], [4]
Obeticholic acid	DM3Q1SM	Primary biliary cholangitis	DB96.1	Approved	[5]

11 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bevacizumab + Trastuzumab	DM9CEI5	Breast cancer	2C60-2C65	Phase 3	[2]
GS-9674	DM936V7	Primary sclerosing cholangitis	DB96.2	Phase 3	[6]
Apomine	DM6B9HP	Osteopetrosis	LD24.10	Phase 2	[7]
EDP-305	DMGJYZ8	Non-alcoholic steatohepatitis	DB92.1	Phase 2	[8]
EYP001	DM5PBLM	Non-alcoholic steatohepatitis	DB92.1	Phase 2	[9]
LJN452	DM3XRUH	Primary biliary cholangitis	DB96.1	Phase 2	[10], [11]
LMB763	DMQOXNL	Diabetic nephropathy	GB61.Z	Phase 2	[12]
MET409	DM89QXT	Non-alcoholic steatohepatitis	DB92.1	Phase 2	[13]
AGN-242266	DMVHPOX	Non-alcoholic steatohepatitis	DB92.1	Phase 1	[14]
PX-102	DMWU682	Hepatic fibrosis	DB93.0	Phase 1	[15]
Turofexorate isopropyl	DM36ONA	Hyperlipidaemia	5C80	Phase 1	[16]

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	[17]
PMID29649907-Compound-10	DMNE9AX	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-11	DMSC9MH	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-12	DMBHT2E	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-13	DMLBQUS	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-14	DMQAV30	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-15	DMMIKFU	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-18	DMBVOZK	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-19	DMFL38V	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-2	DMM4TBH	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-20	DMGNW34	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-21	DMES0UY	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-22	DMXW108	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-23	DMW7T45	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-24	DMUHNS7	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-25	DMALOEW	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-26	DM6O78C	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-27	DMQDGZL	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-28	DMYMKZC	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-29	DMEVZIK	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-3	DMPVSG9	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-30	DM0SY7Q	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-31	DME6H8Q	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-32	DM7E9HA	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-33	DM39HCU	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-34	DMUDKE0	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-35	DMSWJPO	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-36	DMP5KEW	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-37	DM8WKYT	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-38	DMMP09F	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-39	DMI3ELU	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-4	DMO45VP	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-40	DMS6UD2	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-41	DM26IRH	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-42	DMSAD9B	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-44	DMBA2S3	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-5	DMDWSIE	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-8	DMV2D5M	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-9	DMA6H4W	N. A.	N. A.	Patented	[17]
PMID29649907-Compound-INT767	DMA0RI8	N. A.	N. A.	Patented	[17]
PMID30259754-Compound-INT-767	DME0RJ2	N. A.	N. A.	Patented	[10]
PMID30259754-Compound-LY2562175	DMZ5CDY	N. A.	N. A.	Patented	[10]
PMID30259754-Compound-Px-102	DM78IN5	N. A.	N. A.	Patented	[10]
PMID30259754-Compound-pyrrole[2,3-d]azepines	DMVP16K	N. A.	N. A.	Patented	[10]
PMID30259754-Compound-WAY-362450	DMDKSJQ	N. A.	N. A.	Patented	[10]

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	[18]
SKF-97426	DM40HTZ	Hyperlipidaemia	5C80	Discontinued in Phase 2	[19]

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	[20]

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	[7]
12-O-deacetyl-12-epi-19-deoxy-21-hydroxyscalarin	DMKH0OC	Discovery agent	N.A.	Investigative	[4]
22R-hydroxycholesterol	DME8273	Discovery agent	N.A.	Investigative	[21]
AGN-34	DM5ECDM	Discovery agent	N.A.	Investigative	[22]
cholesten	DMKM3WJ	Discovery agent	N.A.	Investigative	[23]
Desmosterol	DMV8SUM	Discovery agent	N.A.	Investigative	[23]
Fexaramine	DMWCLQ5	Discovery agent	N.A.	Investigative	[24]
GW4065	DMFRP7H	Discovery agent	N.A.	Investigative	[2]

Molecular Expression Atlas (MEA) 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

References

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• [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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [4] Scalarane sesterterpenes from a marine sponge of the genus Spongia and their FXR antagonistic activity. J Nat Prod. 2007 Nov;70(11):1691-5.
• [5] 2016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76.
• [6] 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.
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• [8] 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.
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• [13] Clinical pipeline report, company report or official report of Metacrine.
• [14] Clinical pipeline report, company report or official report of AbbVie.
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• [19] 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.
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• [21] 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.
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