Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT36W9O5)

• DOT Name: Leukemia inhibitory factor receptor (LIFR)
• Synonyms: LIF receptor; LIF-R; CD antigen CD118
• Gene Name: LIFR
• Related Disease:
  Obsolete Stve-Wiedemann syndrome
  Stve-Wiedemann syndrome 1
• UniProt ID: LIFR_HUMAN
• PDB ID: 3E0G; 8D6A; 8D74; 8D7R
• Pfam ID: PF00041 ; PF21177 ; PF17971 ; PF18207
• Sequence:
  MMDIYVCLKRPSWMVDNKRMRTASNFQWLLSTFILLYLMNQVNSQKKGAPHDLKCVTNNL
  QVWNCSWKAPSGTGRGTDYEVCIENRSRSCYQLEKTSIKIPALSHGDYEITINSLHDFGS
  STSKFTLNEQNVSLIPDTPEILNLSADFSTSTLYLKWNDRGSVFPHRSNVIWEIKVLRKE
  SMELVKLVTHNTTLNGKDTLHHWSWASDMPLECAIHFVEIRCYIDNLHFSGLEEWSDWSP
  VKNISWIPDSQTKVFPQDKVILVGSDITFCCVSQEKVLSALIGHTNCPLIHLDGENVAIK
  IRNISVSASSGTNVVFTTEDNIFGTVIFAGYPPDTPQQLNCETHDLKEIICSWNPGRVTA
  LVGPRATSYTLVESFSGKYVRLKRAEAPTNESYQLLFQMLPNQEIYNFTLNAHNPLGRSQ
  STILVNITEKVYPHTPTSFKVKDINSTAVKLSWHLPGNFAKINFLCEIEIKKSNSVQEQR
  NVTIKGVENSSYLVALDKLNPYTLYTFRIRCSTETFWKWSKWSNKKQHLTTEASPSKGPD
  TWREWSSDGKNLIIYWKPLPINEANGKILSYNVSCSSDEETQSLSEIPDPQHKAEIRLDK
  NDYIISVVAKNSVGSSPPSKIASMEIPNDDLKIEQVVGMGKGILLTWHYDPNMTCDYVIK
  WCNSSRSEPCLMDWRKVPSNSTETVIESDEFRPGIRYNFFLYGCRNQGYQLLRSMIGYIE
  ELAPIVAPNFTVEDTSADSILVKWEDIPVEELRGFLRGYLFYFGKGERDTSKMRVLESGR
  SDIKVKNITDISQKTLRIADLQGKTSYHLVLRAYTDGGVGPEKSMYVVTKENSVGLIIAI
  LIPVAVAVIVGVVTSILCYRKREWIKETFYPDIPNPENCKALQFQKSVCEGSSALKTLEM
  NPCTPNNVEVLETRSAFPKIEDTEIISPVAERPEDRSDAEPENHVVVSYCPPIIEEEIPN
  PAADEAGGTAQVIYIDVQSMYQPQAKPEEEQENDPVGGAGYKPQMHLPINSTVEDIAAEE
  DLDKTAGYRPQANVNTWNLVSPDSPRSIDSNSEIVSFGSPCSINSRQFLIPPKDEDSPKS
  NGGGWSFTNFFQNKPND
• Function: Signal-transducing molecule. May have a common pathway with IL6ST. The soluble form inhibits the biological activity of LIF by blocking its binding to receptors on target cells.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  JAK-STAT sig.ling pathway (hsa04630)
• Reactome Pathway:
  RUNX1 regulates transcription of genes involved in interleukin signaling (R-HSA-8939247)
  IL-6-type cytokine receptor ligand interactions (R-HSA-6788467)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete Stve-Wiedemann syndrome	DISKSJ1M	Definitive	Autosomal recessive	[1]
Stve-Wiedemann syndrome 1	DISBJ81H	Definitive	Autosomal recessive	[2]

22 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 Leukemia inhibitory factor receptor (LIFR).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Leukemia inhibitory factor receptor (LIFR).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Leukemia inhibitory factor receptor (LIFR).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Leukemia inhibitory factor receptor (LIFR).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leukemia inhibitory factor receptor (LIFR).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Leukemia inhibitory factor receptor (LIFR).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Leukemia inhibitory factor receptor (LIFR).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Leukemia inhibitory factor receptor (LIFR).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Leukemia inhibitory factor receptor (LIFR).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Leukemia inhibitory factor receptor (LIFR).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Leukemia inhibitory factor receptor (LIFR).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Leukemia inhibitory factor receptor (LIFR).	[13]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Leukemia inhibitory factor receptor (LIFR).	[14]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Leukemia inhibitory factor receptor (LIFR).	[15]
Letrozole	DMH07Y3	Approved	Letrozole increases the expression of Leukemia inhibitory factor receptor (LIFR).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Leukemia inhibitory factor receptor (LIFR).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Leukemia inhibitory factor receptor (LIFR).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Leukemia inhibitory factor receptor (LIFR).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Leukemia inhibitory factor receptor (LIFR).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Leukemia inhibitory factor receptor (LIFR).	[22]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Leukemia inhibitory factor receptor (LIFR).	[23]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Leukemia inhibitory factor receptor (LIFR).	[24]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Gentamicin	DMKINJO	Approved	Gentamicin decreases the degradation of Leukemia inhibitory factor receptor (LIFR).	[16]

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 decreases the methylation of Leukemia inhibitory factor receptor (LIFR).	[20]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome. Am J Hum Genet. 2004 Feb;74(2):298-305. doi: 10.1086/381715. Epub 2004 Jan 21.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. Toxicol In Vitro. 2015 Sep;29(6):1231-9. doi: 10.1016/j.tiv.2014.10.012. Epub 2014 Oct 24.
• [7] 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.
• [8] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [9] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [15] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [16] In vitro readthrough of termination codons by gentamycin in the Stve-Wiedemann Syndrome. Eur J Hum Genet. 2010 Jan;18(1):130-2. doi: 10.1038/ejhg.2009.122.
• [17] Clomiphene citrate versus letrozole: molecular analysis of the endometrium in women with polycystic ovary syndrome. Fertil Steril. 2011 Oct;96(4):1051-6. doi: 10.1016/j.fertnstert.2011.07.1092.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [21] Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014 May;13(5):1142-54.
• [22] 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.
• [23] 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.
• [24] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.