Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9H7G0C)

• DOT Name: Leptin receptor (LEPR)
• Synonyms: LEP-R; HuB219; OB receptor; OB-R; CD antigen CD295
• Gene Name: LEPR
• Related Disease: Obesity due to leptin receptor gene deficiency
• UniProt ID: LEPR_HUMAN
• PDB ID: 3V6O; 6E2P; 7Z3Q; 8AVE; 8AVF; 8AVO
• Pfam ID: PF06328 ; PF18589
• Sequence:
  MICQKFCVVLLHWEFIYVITAFNLSYPITPWRFKLSCMPPNSTYDYFLLPAGLSKNTSNS
  NGHYETAVEPKFNSSGTHFSNLSKTTFHCCFRSEQDRNCSLCADNIEGKTFVSTVNSLVF
  QQIDANWNIQCWLKGDLKLFICYVESLFKNLFRNYNYKVHLLYVLPEVLEDSPLVPQKGS
  FQMVHCNCSVHECCECLVPVPTAKLNDTLLMCLKITSGGVIFQSPLMSVQPINMVKPDPP
  LGLHMEITDDGNLKISWSSPPLVPFPLQYQVKYSENSTTVIREADKIVSATSLLVDSILP
  GSSYEVQVRGKRLDGPGIWSDWSTPRVFTTQDVIYFPPKILTSVGSNVSFHCIYKKENKI
  VPSKEIVWWMNLAEKIPQSQYDVVSDHVSKVTFFNLNETKPRGKFTYDAVYCCNEHECHH
  RYAELYVIDVNINISCETDGYLTKMTCRWSTSTIQSLAESTLQLRYHRSSLYCSDIPSIH
  PISEPKDCYLQSDGFYECIFQPIFLLSGYTMWIRINHSLGSLDSPPTCVLPDSVVKPLPP
  SSVKAEITINIGLLKISWEKPVFPENNLQFQIRYGLSGKEVQWKMYEVYDAKSKSVSLPV
  PDLCAVYAVQVRCKRLDGLGYWSNWSNPAYTVVMDIKVPMRGPEFWRIINGDTMKKEKNV
  TLLWKPLMKNDSLCSVQRYVINHHTSCNGTWSEDVGNHTKFTFLWTEQAHTVTVLAINSI
  GASVANFNLTFSWPMSKVNIVQSLSAYPLNSSCVIVSWILSPSDYKLMYFIIEWKNLNED
  GEIKWLRISSSVKKYYIHDHFIPIEKYQFSLYPIFMEGVGKPKIINSFTQDDIEKHQSDA
  GLYVIVPVIISSSILLLGTLLISHQRMKKLFWEDVPNPKNCSWAQGLNFQKPETFEHLFI
  KHTASVTCGPLLLEPETISEDISVDTSWKNKDEMMPTTVVSLLSTTDLEKGSVCISDQFN
  SVNFSEAEGTEVTYEDESQRQPFVKYATLISNSKPSETGEEQGLINSSVTKCFSSKNSPL
  KDSFSNSSWEIEAQAFFILSDQHPNIISPHLTFSEGLDELLKLEGNFPEENNDKKSIYYL
  GVTSIKKRESGVLLTDKSRVSCPFPAPCLFTDIRVLQDSCSHFVENNINLGTSSKKTFAS
  YMPQFQTCSTQTHKIMENKMCDLTV
• Function: Receptor for hormone LEP/leptin (Probable). On ligand binding, mediates LEP central and peripheral effects through the activation of different signaling pathways such as JAK2/STAT3 and MAPK cascade/FOS. In the hypothalamus, LEP acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic and affects innate and adaptive immunity. Control of energy homeostasis and melanocortin production (stimulation of POMC and full repression of AgRP transcription) is mediated by STAT3 signaling, whereas distinct signals regulate NPY and the control of fertility, growth and glucose homeostasis. Involved in the regulation of counter-regulatory response to hypoglycemia by inhibiting neurons of the parabrachial nucleus. Has a specific effect on T lymphocyte responses, differentially regulating the proliferation of naive and memory T -ells. Leptin increases Th1 and suppresses Th2 cytokine production; [Isoform A]: May transport LEP across the blood-brain barrier. Binds LEP and mediates LEP endocytosis. Does not induce phosphorylation of and activate STAT3; [Isoform E]: Antagonizes Isoform A and isoform B-mediated LEP binding and endocytosis.
• Tissue Specificity: Isoform A is expressed in fetal liver and in hematopoietic tissues and choroid plexus. In adults highest expression in heart, liver, small intestine, prostate and ovary. Low level in lung and kidney. Isoform B is highly expressed in hypothalamus, but also in skeletal muscle. Detected in fundic and antral epithelial cells of the gastric mucosa . Isoform B and isoform A are expressed by NK cells (at protein level) .
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Neuroactive ligand-receptor interaction (hsa04080)
  AMPK sig.ling pathway (hsa04152)
  JAK-STAT sig.ling pathway (hsa04630)
  Adipocytokine sig.ling pathway (hsa04920)
  Non-alcoholic fatty liver disease (hsa04932)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obesity due to leptin receptor gene deficiency	DISFLGUV	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Simvastatin	DM30SGU	Approved	Leptin receptor (LEPR) affects the response to substance of Simvastatin.	[18]
Topotecan	DMP6G8T	Approved	Leptin receptor (LEPR) affects the response to substance of Topotecan.	[19]

16 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 Leptin receptor (LEPR).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Leptin receptor (LEPR).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leptin receptor (LEPR).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Leptin receptor (LEPR).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Leptin receptor (LEPR).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Leptin receptor (LEPR).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Leptin receptor (LEPR).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Leptin receptor (LEPR).	[10]
Gefitinib	DM15F0X	Approved	Gefitinib decreases the expression of Leptin receptor (LEPR).	[11]
Ketamine	DMT5HA4	Approved	Ketamine decreases the expression of Leptin receptor (LEPR).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Leptin receptor (LEPR).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Leptin receptor (LEPR).	[14]
AMEP	DMFELMQ	Phase 1	AMEP decreases the expression of Leptin receptor (LEPR).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Leptin receptor (LEPR).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Leptin receptor (LEPR).	[5]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Leptin receptor (LEPR).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Leptin receptor (LEPR).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Leptin receptor (LEPR).	[16]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] [Quercetin affects leptin and its receptor in human gastric cancer MGC-803 cells and JAK-STAT pathway]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2012 Jan;28(1):12-6.
• [8] Regulation of leptin receptor expression in human papillary thyroid cancer cells. Biomed Pharmacother. 2012 Sep;66(6):469-73. doi: 10.1016/j.biopha.2012.03.008. Epub 2012 Mar 31.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer. Oncol Rep. 2006 Jun;15(6):1453-60.
• [12] Lipoxin A4 methyl ester attenuated ketamine-induced neurotoxicity in SH-SY5Y cells via regulating leptin pathway. Toxicol In Vitro. 2023 Jun;89:105581. doi: 10.1016/j.tiv.2023.105581. Epub 2023 Mar 11.
• [13] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [14] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [15] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Leptin receptor polymorphism is associated with serum lipid levels and impairment of cholesterol lowering effect by simvastatin in Japanese men. Diabetes Res Clin Pract. 2003 Dec;62(3):169-75. doi: 10.1016/s0168-8227(03)00163-3.
• [19] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.