Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTXA6PH)

• DTT Name: Oxysterols receptor LXR-beta (NR1H2)
• Synonyms: Ubiquitously-expressed nuclear receptor; Nuclear receptor subfamily 1 group H member 2; Nuclear receptor NER; Nuclear orphan receptor LXR-beta; NER; Liver X receptor beta; LXRbeta; LXRB
• Gene Name: NR1H2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: NR1H2_HUMAN
• TTD ID: T13714
• Sequence:
  MSSPTTSSLDTPLPGNGPPQPGAPSSSPTVKEEGPEPWPGGPDPDVPGTDEASSACSTDW
  VIPDPEEEPERKRKKGPAPKMLGHELCRVCGDKASGFHYNVLSCEGCKGFFRRSVVRGGA
  RRYACRGGGTCQMDAFMRRKCQQCRLRKCKEAGMREQCVLSEEQIRKKKIRKQQQESQSQ
  SQSPVGPQGSSSSASGPGASPGGSEAGSQGSGEGEGVQLTAAQELMIQQLVAAQLQCNKR
  SFSDQPKVTPWPLGADPQSRDARQQRFAHFTELAIISVQEIVDFAKQVPGFLQLGREDQI
  ALLKASTIEIMLLETARRYNHETECITFLKDFTYSKDDFHRAGLQVEFINPIFEFSRAMR
  RLGLDDAEYALLIAINIFSADRPNVQEPGRVEALQQPYVEALLSYTRIKRPQDQLRFPRM
  LMKLVSLRTLSSVHSEQVFALRLQDKKLPPLLSEIWDVHE
• Function: Binds preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence 5'-AGGTCA-3' and 4-nt spacing (DR-4). Regulates cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8; DLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism. Plays an anti-inflammatory role during the hepatic acute phase response by acting as a corepressor: inhibits the hepatic acute phase response by preventing dissociation of the N-Cor corepressor complex. Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity.
• KEGG Pathway: Insulin resistance (hsa04931)
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
VTB-38543	DMNY3J0	Atopic dermatitis	EA80	Phase 2	[1]

25 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	[2]
12-dehydroxyriccardin C	DMTOSXF	Discovery agent	N.A.	Investigative	[2]
17-dehydroxyriccardin C	DM7UHJS	Discovery agent	N.A.	Investigative	[2]
2-Benzyl-3-phenyl-7-(trifluoromethyl)-2H-indazole	DMANTCY	Discovery agent	N.A.	Investigative	[3]
2-benzyl-4,5,6,7-tetrachloroisoindoline-1,3-dione	DMH76SO	Discovery agent	N.A.	Investigative	[4]
2-Propanol, Isopropanol	DML5O0H	Discovery agent	N.A.	Investigative	[5]
22R-hydroxycholesterol	DME8273	Discovery agent	N.A.	Investigative	[6]
24(S), 25-epoxycholesterol	DMW2KI5	Discovery agent	N.A.	Investigative	[7]
24(S)-hydroxycholesterol	DMGMWA6	Discovery agent	N.A.	Investigative	[8]
27-hydroxycholesterol	DM2L6OZ	Discovery agent	N.A.	Investigative	[9]
4,17-dehydroxyriccardin C	DMIZ0GO	Discovery agent	N.A.	Investigative	[2]
4-dehydroxyriccardin C	DM93DQG	Discovery agent	N.A.	Investigative	[2]
acetyl-podocarpic dimer	DMGTPFY	Discovery agent	N.A.	Investigative	[10]
AZ12260493	DMQ5H2V	Discovery agent	N.A.	Investigative	[11]
Benzenesulfonyl	DMMBYGE	Discovery agent	N.A.	Investigative	[5]
desmosterol	DMV8SUM	Discovery agent	N.A.	Investigative	[12]
GSK-9772	DM4WS3R	Discovery agent	N.A.	Investigative	[13]
GSK2033	DM9GPAU	Discovery agent	N.A.	Investigative	[14]
GW-3965	DMG60ET	Major depressive disorder	6A70.3	Investigative	[3]
L-783483	DM6OTGE	Discovery agent	N.A.	Investigative	[15]
N-{4-[2-(3-Methoxyphenyl)ethyl]phenyl}phthalimide	DMZ4N7Q	Discovery agent	N.A.	Investigative	[16]
Riccardin C	DM6MYGX	Discovery agent	N.A.	Investigative	[2]
SR9238	DM2WIGO	Discovery agent	N.A.	Investigative	[17]
WAY-214950	DM8ODI7	Discovery agent	N.A.	Investigative	[3]
WAY-254011	DMC83HA	Discovery agent	N.A.	Investigative	[18]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] 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.
• [3] 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.
• [4] 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.
• [5] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [6] An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996 Oct 24;383(6602):728-31.
• [7] Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis. Nat Chem Biol. 2013 Feb;9(2):126-33.
• [8] Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem. 1997 Feb 7;272(6):3137-40.
• [9] 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem. 2001 Oct 19;276(42):38378-87.
• [10] 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.
• [11] 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: 601).
• [12] Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands. J Biol Chem. 2006 Sep 22;281(38):27816-26.
• [13] 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.
• [14] Discovery of tertiary sulfonamides as potent liver X receptor antagonists. J Med Chem. 2010 Apr 22;53(8):3412-6.
• [15] A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7alpha-hydroxylase (CYP7a). Endocrinology. 2002 Jul;143(7):2548-58.
• [16] 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.
• [17] A liver-selective LXR inverse agonist that suppresses hepatic steatosis. ACS Chem Biol. 2013 Mar 15;8(3):559-67.
• [18] 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.