Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Oxysterols receptor LXR-alpha (NR1H3)
• Synonyms: Nuclear receptor subfamily 1 group H member 3; Nuclear receptor LXRalpha; Nuclear orphan receptor LXR-alpha; Liver X receptor alpha; LXRalpha; LXRA
• Gene Name: NR1H3
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: NR1H3_HUMAN
• TTD ID: T52297
• Sequence:
  MSLWLGAPVPDIPPDSAVELWKPGAQDASSQAQGGSSCILREEARMPHSAGGTAGVGLEA
  AEPTALLTRAEPPSEPTEIRPQKRKKGPAPKMLGNELCSVCGDKASGFHYNVLSCEGCKG
  FFRRSVIKGAHYICHSGGHCPMDTYMRRKCQECRLRKCRQAGMREECVLSEEQIRLKKLK
  RQEEEQAHATSLPPRASSPPQILPQLSPEQLGMIEKLVAAQQQCNRRSFSDRLRVTPWPM
  APDPHSREARQQRFAHFTELAIVSVQEIVDFAKQLPGFLQLSREDQIALLKTSAIEVMLL
  ETSRRYNPGSESITFLKDFSYNREDFAKAGLQVEFINPIFEFSRAMNELQLNDAEFALLI
  AISIFSADRPNVQDQLQVERLQHTYVEALHAYVSIHHPHDRLMFPRMLMKLVSLRTLSSV
  HSEQVFALRLQDKKLPPLLSEIWDVHE
• Function: Interaction with retinoic acid receptor (RXR) shifts RXR from its role as a silent DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXRES. LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half-sites spaced by four nucleotides. Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism. Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity.
• KEGG Pathway:
  PPAR signaling pathway (hsa03320)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Hepatitis C (hsa05160)
• Reactome Pathway:
  Nuclear Receptor transcription pathway (R-HSA-383280)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  VLDLR internalisation and degradation (R-HSA-8866427)
  NR1H2 & NR1H3 regulate gene expression linked to lipogenesis (R-HSA-9029558)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  NR1H2 & NR1H3 regulate gene expression to limit cholesterol uptake (R-HSA-9031525)
  NR1H2 & NR1H3 regulate gene expression linked to triglyceride lipolysis in adipose (R-HSA-9031528)
  NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis (R-HSA-9623433)
  NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis (R-HSA-9632974)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DTT

9 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
67S	DMJL1MB	N. A.	N. A.	Patented	[2]
BDBM50177012	DM52IQF	N. A.	N. A.	Patented	[2]
BDBM50177019	DMEL28G	N. A.	N. A.	Patented	[2]
US9006244, E1	DMBF1C0	N. A.	N. A.	Patented	[3]
US9006244, E2a	DMPDF9B	N. A.	N. A.	Patented	[3]
US9006244, E2b	DMP0TBO	N. A.	N. A.	Patented	[3]
US9073931, E1	DM2Z43I	N. A.	N. A.	Patented	[4]
US9073931, E2	DMK9FJG	N. A.	N. A.	Patented	[4]
US9073931, E3	DMCYM8P	N. A.	N. A.	Patented	[4]

32 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
12,17-dehydroxyriccardin C	DMAUPQR	Discovery agent	N.A.	Investigative	[5]
12-dehydroxyriccardin C	DMTOSXF	Discovery agent	N.A.	Investigative	[5]
17-dehydroxyriccardin C	DM7UHJS	Discovery agent	N.A.	Investigative	[5]
2-(2-hexylphenyl)isoindoline-1,3-dione	DMSI41E	Discovery agent	N.A.	Investigative	[5]
2-(2-phenethylphenyl)isoindoline-1,3-dione	DM5NLQE	Discovery agent	N.A.	Investigative	[6]
2-Benzyl-3-phenyl-7-(trifluoromethyl)-2H-indazole	DMANTCY	Discovery agent	N.A.	Investigative	[7]
2-benzyl-4,5,6,7-tetrachloroisoindoline-1,3-dione	DMH76SO	Discovery agent	N.A.	Investigative	[8]
22R-hydroxycholesterol	DME8273	Discovery agent	N.A.	Investigative	[9]
24(S), 25-epoxycholesterol	DMW2KI5	Discovery agent	N.A.	Investigative	[10]
24(S)-hydroxycholesterol	DMGMWA6	Discovery agent	N.A.	Investigative	[11]
27-hydroxycholesterol	DM2L6OZ	Discovery agent	N.A.	Investigative	[12]
4,12,17-dehydroxyriccardin C	DM1XTJC	Discovery agent	N.A.	Investigative	[5]
4,17-dehydroxyriccardin C	DMIZ0GO	Discovery agent	N.A.	Investigative	[5]
4-dehydroxyriccardin C	DM93DQG	Discovery agent	N.A.	Investigative	[5]
5-chloro-2-(4-phenylbutyl)isoindoline-1,3-dione	DM9QBAZ	Discovery agent	N.A.	Investigative	[8]
acetyl-podocarpic dimer	DMGTPFY	Discovery agent	N.A.	Investigative	[13]
AZ12260493	DMQ5H2V	Discovery agent	N.A.	Investigative	[14]
desmosterol	DMV8SUM	Discovery agent	N.A.	Investigative	[15]
GSK-9772	DM4WS3R	Discovery agent	N.A.	Investigative	[16]
GSK2033	DM9GPAU	Discovery agent	N.A.	Investigative	[17]
Guttiferone I	DMBXGVH	Discovery agent	N.A.	Investigative	[18]
GW-3965	DMG60ET	Major depressive disorder	6A70.3	Investigative	[7]
L-783483	DM6OTGE	Discovery agent	N.A.	Investigative	[19]
N-{4-[2-(3-Hydroxyphenyl)ethyl]phenyl}phthalimide	DMO3VLJ	Discovery agent	N.A.	Investigative	[6]
N-{4-[2-(3-Methoxyphenyl)ethyl]phenyl}phthalimide	DMZ4N7Q	Discovery agent	N.A.	Investigative	[6]
N-{4-[2-(4-Hydroxyphenyl)ethyl]phenyl}phthalimide	DMXU5IS	Discovery agent	N.A.	Investigative	[6]
N-{4-[2-(4-Methoxyphenyl)ethyl]phenyl}phthalimide	DM0S71O	Discovery agent	N.A.	Investigative	[6]
paxilline	DMPF2N1	Discovery agent	N.A.	Investigative	[20]
Riccardin C	DM6MYGX	Discovery agent	N.A.	Investigative	[5]
SR9238	DM2WIGO	Discovery agent	N.A.	Investigative	[1]
WAY-214950	DM8ODI7	Discovery agent	N.A.	Investigative	[7]
WAY-254011	DMC83HA	Discovery agent	N.A.	Investigative	[21]

References

• [1] A liver-selective LXR inverse agonist that suppresses hepatic steatosis. ACS Chem Biol. 2013 Mar 15;8(3):559-67.
• [2] Piperazine derivatives as liver X receptor modulators. US10144715.
• [3] Liver X receptor modulators. US9006244.
• [4] Liver X receptor modulators. US9073931.
• [5] Co-existence of alpha-glucosidase-inhibitory and liver X receptor-regulatory activities and their separation by structural development. Bioorg Med Chem. 2008 Apr 15;16(8):4272-85.
• [6] Separation of alpha-glucosidase-inhibitory and liver X receptor-antagonistic activities of phenethylphenyl phthalimide analogs and generation of LX... Bioorg Med Chem. 2009 Jul 15;17(14):5001-14.
• [7] Indazole-based liver X receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic tr... J Med Chem. 2008 Nov 27;51(22):7161-8.
• [8] Liver X receptor antagonists with a phthalimide skeleton derived from thalidomide-related glucosidase inhibitors. Bioorg Med Chem Lett. 2007 Jul 15;17(14):3957-61.
• [9] An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996 Oct 24;383(6602):728-31.
• [10] Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis. Nat Chem Biol. 2013 Feb;9(2):126-33.
• [11] Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem. 1997 Feb 7;272(6):3137-40.
• [12] 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem. 2001 Oct 19;276(42):38378-87.
• [13] A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux. J Biol Chem. 2002 Mar 22;277(12):10021-7.
• [14] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 602).
• [15] Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands. J Biol Chem. 2006 Sep 22;281(38):27816-26.
• [16] Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity. J Med Chem. 2008 Sep 25;51(18):5758-65.
• [17] Discovery of tertiary sulfonamides as potent liver X receptor antagonists. J Med Chem. 2010 Apr 22;53(8):3412-6.
• [18] Guttiferone I, a new prenylated benzophenone from Garcinia humilis as a liver X receptor ligand. J Nat Prod. 2005 Apr;68(4):617-9.
• [19] A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7alpha-hydroxylase (CYP7a). Endocrinology. 2002 Jul;143(7):2548-58.
• [20] A natural product ligand of the oxysterol receptor, liver X receptor. J Pharmacol Exp Ther. 2003 Oct;307(1):291-6.
• [21] Discovery and SAR of cinnolines/quinolines as liver X receptor (LXR) agonists with binding selectivity for LXRbeta. Bioorg Med Chem. 2009 May 15;17(10):3519-27.