Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT6PEUO)

• DTT Name: Retinoic acid receptor RXR-alpha (RXRA)
• Synonyms: Retinoid X receptor alpha; RXRalpha; Nuclear receptor subfamily 2 group B member 1; NR2B1
• Gene Name: RXRA
• DTT Type: Successful target; [1]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: RXRA_HUMAN
• TTD ID: T13726
• Sequence:
  MDTKHFLPLDFSTQVNSSLTSPTGRGSMAAPSLHPSLGPGIGSPGQLHSPISTLSSPING
  MGPPFSVISSPMGPHSMSVPTTPTLGFSTGSPQLSSPMNPVSSSEDIKPPLGLNGVLKVP
  AHPSGNMASFTKHICAICGDRSSGKHYGVYSCEGCKGFFKRTVRKDLTYTCRDNKDCLID
  KRQRNRCQYCRYQKCLAMGMKREAVQEERQRGKDRNENEVESTSSANEDMPVERILEAEL
  AVEPKTETYVEANMGLNPSSPNDPVTNICQAADKQLFTLVEWAKRIPHFSELPLDDQVIL
  LRAGWNELLIASFSHRSIAVKDGILLATGLHVHRNSAHSAGVGAIFDRVLTELVSKMRDM
  QMDKTELGCLRAIVLFNPDSKGLSNPAEVEALREKVYASLEAYCKHKYPEQPGRFAKLLL
  RLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLEAPHQMT
• Function: Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes. Receptor for retinoic acid.
• KEGG Pathway:
  PPAR signaling pathway (hsa03320)
  PI3K-Akt signaling pathway (hsa04151)
  Thyroid hormone signaling pathway (hsa04919)
  Adipocytokine signaling pathway (hsa04920)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Bile secretion (hsa04976)
  Hepatitis C (hsa05160)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Thyroid cancer (hsa05216)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
• Reactome Pathway:
  BMAL1 (R-HSA-1368108)
  Recycling of bile acids and salts (R-HSA-159418)
  PPARA activates gene expression (R-HSA-1989781)
  Import of palmitoyl-CoA into the mitochondrial matrix (R-HSA-200425)
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)
  Regulation of pyruvate dehydrogenase (PDH) complex (R-HSA-204174)
  Endogenous sterols (R-HSA-211976)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha) (R-HSA-400206)
  Circadian Clock (R-HSA-400253)
  RORA activates gene expression (R-HSA-1368082)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alitretinoin	DMME8LH	Kaposi sarcoma	2B57	Approved	[1]
Bexarotene	DMOBIKY	Cutaneous T-cell lymphoma	2B01	Approved	[2]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(5BETA)-PREGNANE-3,20-DIONE	DMVQ6RN	Discovery agent	N.A.	Investigative	[3]
2-chloro-5-nitro-N-phenylbenzamide	DMUGQIV	Discovery agent	N.A.	Investigative	[3]
AGN-34	DM5ECDM	Discovery agent	N.A.	Investigative	[4]
CD3254	DM38MU1	Discovery agent	N.A.	Investigative	[5]
LG100754	DMEK4FY	Discovery agent	N.A.	Investigative	[6]
methoprene acid	DM58A0W	Discovery agent	N.A.	Investigative	[7]
PA451	DMTGZ3E	Discovery agent	N.A.	Investigative	[8]
phytanic acid	DMSZ1RB	Discovery agent	N.A.	Investigative	[9]
Tributylstannanyl	DMHN7CB	Discovery agent	N.A.	Investigative	[3]
UVI3003	DM95UI1	Discovery agent	N.A.	Investigative	[10]

References

• [1] Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):30-4.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [4] Farnesoid X receptor: from structure to potential clinical applications. J Med Chem. 2005 Aug 25;48(17):5383-403.
• [5] Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature. 2002 Jan 10;415(6868):187-92.
• [6] The rexinoid LG100754 is a novel RXR:PPARgamma agonist and decreases glucose levels in vivo. Mol Endocrinol. 2001 Aug;15(8):1360-9.
• [7] Activation of mammalian retinoid X receptors by the insect growth regulator methoprene. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):6157-60.
• [8] Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions. J Med Chem. 2002 Aug 1;45(16):3327-30.
• [9] Phytanic acid is a retinoid X receptor ligand. Eur J Biochem. 1996 Feb 15;236(1):328-33.
• [10] Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators thro... J Biol Chem. 2005 Jan 14;280(2):1625-33.