Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1BJE8K)

• DOT Name: Retinoic acid receptor responder protein 2 (RARRES2)
• Synonyms: Chemerin; RAR-responsive protein TIG2; Tazarotene-induced gene 2 protein
• Gene Name: RARRES2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Advanced cancer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Bipolar disorder
  Cardiovascular disease
  Carotid stenosis
  Congestive heart failure
  Coronary heart disease
  Cutaneous squamous cell carcinoma
  Gastric cancer
  Granulosa cell tumor
  Hepatocellular carcinoma
  Irritable bowel syndrome
  Major depressive disorder
  Metabolic disorder
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Osteoarthritis
  Periodontitis
  Prostate cancer
  Prostate carcinoma
  Psoriasis
  Rheumatoid arthritis
  Squamous cell carcinoma
  Stomach cancer
  Type-1/2 diabetes
  Coronary atherosclerosis
  Diabetic kidney disease
  Liver cirrhosis
  Non-alcoholic fatty liver disease
  Periodontal disease
  Polycystic ovarian syndrome
  Adrenocortical carcinoma
  Aplasia cutis congenita
  Arthritis
  Chronic kidney disease
  Corpus callosum, agenesis of
  Inflammatory bowel disease
  Melanoma
  Systemic sclerosis
• UniProt ID: RARR2_HUMAN
• PDB ID: 7YKD
• Sequence:
  MRRLLIPLALWLGAVGVGVAELTEAQRRGLQVALEEFHKHPPVQWAFQETSVESAVDTPF
  PAGIFVRLEFKLQQTSCRKRDWKKPECKVRPNGRKRKCLACIKLGSEDKVLGRLVHCPIE
  TQVLREAEEHQETQCLRVQRAGEDPHSFYFPGQFAFSKALPRS
• Function: Adipocyte-secreted protein (adipokine) that regulates adipogenesis, metabolism and inflammation through activation of the chemokine-like receptor 1 (CMKLR1). Acts also as a ligand for CMKLR2. Can also bind to C-C chemokine receptor-like 2 (CCRL2), but with a lower affinity than it does to CMKLR1 or CMKLR2. Positively regulates adipocyte differentiation, modulates the expression of adipocyte genes involved in lipid and glucose metabolism and might play a role in angiogenesis, a process essential for the expansion of white adipose tissue. Also acts as a pro-inflammatory adipokine, causing an increase in secretion of pro-inflammatory and prodiabetic adipokines, which further impair adipose tissue metabolic function and have negative systemic effects including impaired insulin sensitivity, altered glucose and lipid metabolism, and a decrease in vascular function in other tissues. Can have both pro- and anti-inflammatory properties depending on the modality of enzymatic cleavage by different classes of proteases. Acts as a chemotactic factor for leukocyte populations expressing CMKLR1, particularly immature plasmacytoid dendritic cells, but also immature myeloid DCs, macrophages and natural killer cells. Exerts an anti-inflammatory role by preventing TNF/TNFA-induced VCAM1 expression and monocytes adhesion in vascular endothelial cells. The effect is mediated via inhibiting activation of NF-kappa-B and CRK/p38 through stimulation of AKT1/NOS3 signaling and nitric oxide production. Its dual role in inflammation and metabolism might provide a link between chronic inflammation and obesity, as well as obesity-related disorders such as type 2 diabetes and cardiovascular disease. Exhibits an antimicrobial function in the skin.
• Tissue Specificity: Expressed at the highest levels in placenta, liver, and white adipose tissue (WAT), and to a lesser extent in many other tissues such as lung, brown adipose tissue, heart, ovary, kidney, skeletal muscle and pancreas. Within WAT, expression is enriched in adipocytes as compared to the stromal vascular fraction. Expression and secretion increases dramatically with adipogenesis. Highly expressed in skin (basal and suprabasal layers of the epidermis, hair follicles and endothelial cells). Expression is elevated in numerous metabolic and inflammatory diseases including psoriasis, obesity, type 2 diabetes, metabolic syndrome and cardiovascular disease.
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[5]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[6]
Carotid stenosis	DISZA8D0	Strong	Altered Expression	[7]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[8]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[9]
Cutaneous squamous cell carcinoma	DIS3LXUG	Strong	Biomarker	[10]
Gastric cancer	DISXGOUK	Strong	Biomarker	[11]
Granulosa cell tumor	DISKWVAB	Strong	Altered Expression	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Irritable bowel syndrome	DIS27206	Strong	Biomarker	[14]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[5]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[17]
Obesity	DIS47Y1K	Strong	Biomarker	[18]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[19]
Periodontitis	DISI9JOI	Strong	Altered Expression	[20]
Prostate cancer	DISF190Y	Strong	Biomarker	[21]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[21]
Psoriasis	DIS59VMN	Strong	Biomarker	[22]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[23]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[11]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[24]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[6]
Diabetic kidney disease	DISJMWEY	moderate	Biomarker	[25]
Liver cirrhosis	DIS4G1GX	moderate	Altered Expression	[26]
Non-alcoholic fatty liver disease	DISDG1NL	moderate	Biomarker	[27]
Periodontal disease	DISJQHVN	moderate	Biomarker	[28]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Altered Expression	[29]
Adrenocortical carcinoma	DISZF4HX	Limited	Biomarker	[30]
Aplasia cutis congenita	DISMDAYM	Limited	Biomarker	[30]
Arthritis	DIST1YEL	Limited	Biomarker	[31]
Chronic kidney disease	DISW82R7	Limited	Biomarker	[32]
Corpus callosum, agenesis of	DISO9P40	Limited	Biomarker	[30]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[33]
Melanoma	DIS1RRCY	Limited	Biomarker	[10]
Systemic sclerosis	DISF44L6	Limited	Biomarker	[34]

21 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[35]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[36]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[38]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[39]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[40]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[41]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[42]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[43]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[44]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[45]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[46]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[45]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[48]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[45]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[49]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[51]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[52]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[12]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Retinoic acid receptor responder protein 2 (RARRES2).	[53]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retinoic acid receptor responder protein 2 (RARRES2).	[50]

References

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