Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC0FB7T)

• DOT Name: Protein sel-1 homolog 1 (SEL1L)
• Synonyms: Suppressor of lin-12-like protein 1; Sel-1L
• Gene Name: SEL1L
• Related Disease:
  Pancreatic cancer
  Parkinson disease
  Advanced cancer
  Alzheimer disease
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Central diabetes insipidus
  Cerebellar ataxia
  Cervical cancer
  Cervical carcinoma
  Dementia
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Glioma
  Graves disease
  Hepatitis C virus infection
  Multinodular goiter
  Neoplasm of esophagus
  Neuroblastoma
  Pancreatic adenocarcinoma
  Pancreatic ductal carcinoma
  Patent ductus arteriosus
  Carcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Non-small-cell lung cancer
  Obesity
  Prostate cancer
  Prostate carcinoma
  Adenocarcinoma
  Adult lymphoma
  Amyotrophic lateral sclerosis
  Granular corneal dystrophy type II
  Leukemia
  Lymphoma
  Pediatric lymphoma
• UniProt ID: SE1L1_HUMAN
• Pfam ID: PF00040 ; PF08238
• Sequence:
  MRVRIGLTLLLCAVLLSLASASSDEEGSQDESLDSKTTLTSDESVKDHTTAGRVVAGQIF
  LDSEESELESSIQEEEDSLKSQEGESVTEDISFLESPNPENKDYEEPKKVRKPALTAIEG
  TAHGEPCHFPFLFLDKEYDECTSDGREDGRLWCATTYDYKADEKWGFCETEEEAAKRRQM
  QEAEMMYQTGMKILNGSNKKSQKREAYRYLQKAASMNHTKALERVSYALLFGDYLPQNIQ
  AAREMFEKLTEEGSPKGQTALGFLYASGLGVNSSQAKALVYYTFGALGGNLIAHMVLGYR
  YWAGIGVLQSCESALTHYRLVANHVASDISLTGGSVVQRIRLPDEVENPGMNSGMLEEDL
  IQYYQFLAEKGDVQAQVGLGQLHLHGGRGVEQNHQRAFDYFNLAANAGNSHAMAFLGKMY
  SEGSDIVPQSNETALHYFKKAADMGNPVGQSGLGMAYLYGRGVQVNYDLALKYFQKAAEQ
  GWVDGQLQLGSMYYNGIGVKRDYKQALKYFNLASQGGHILAFYNLAQMHASGTGVMRSCH
  TAVELFKNVCERGRWSERLMTAYNSYKDGDYNAAVIQYLLLAEQGYEVAQSNAAFILDQR
  EASIVGENETYPRALLHWNRAASQGYTVARIKLGDYHFYGFGTDVDYETAFIHYRLASEQ
  QHSAQAMFNLGYMHEKGLGIKQDIHLAKRFYDMAAEASPDAQVPVFLALCKLGVVYFLQY
  IRETNIRDMFTQLDMDQLLGPEWDLYLMTIIALLLGTVIAYRQRQHQDMPAPRPPGPRPA
  PPQQEGPPEQQPPQ
• Function: Plays a role in the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins. Enhances SYVN1 stability. Plays a role in LPL maturation and secretion. Required for normal differentiation of the pancreas epithelium, and for normal exocrine function and survival of pancreatic cells. May play a role in Notch signaling.
• Tissue Specificity: Highly expressed in pancreas.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  ABC-family proteins mediated transport (R-HSA-382556)
  Hedgehog ligand biogenesis (R-HSA-5358346)
  Hh mutants are degraded by ERAD (R-HSA-5362768)
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  ER Quality Control Compartment (ERQC) (R-HSA-901032)
  Pre-NOTCH Processing in Golgi (R-HSA-1912420)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pancreatic cancer	DISJC981	Definitive	Biomarker	[1]
Parkinson disease	DISQVHKL	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[1]
Central diabetes insipidus	DISJ4P9O	Strong	Biomarker	[8]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[9]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[10]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[10]
Dementia	DISXL1WY	Strong	Genetic Variation	[11]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[5]
Glioma	DIS5RPEH	Strong	Altered Expression	[12]
Graves disease	DISU4KOQ	Strong	Biomarker	[13]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[14]
Multinodular goiter	DISZQJH7	Strong	Biomarker	[13]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[1]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[2]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[15]
Pancreatic ductal carcinoma	DIS26F9Q	Strong	Altered Expression	[16]
Patent ductus arteriosus	DIS9P8YS	Strong	Altered Expression	[16]
Carcinoma	DISH9F1N	moderate	Altered Expression	[15]
Lung cancer	DISCM4YA	moderate	Altered Expression	[17]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[17]
Lung neoplasm	DISVARNB	moderate	Altered Expression	[17]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Altered Expression	[17]
Obesity	DIS47Y1K	moderate	Biomarker	[18]
Prostate cancer	DISF190Y	moderate	Biomarker	[17]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[17]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[17]
Adult lymphoma	DISK8IZR	Limited	Genetic Variation	[19]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Altered Expression	[20]
Granular corneal dystrophy type II	DISAEE20	Limited	Altered Expression	[21]
Leukemia	DISNAKFL	Limited	Altered Expression	[19]
Lymphoma	DISN6V4S	Limited	Biomarker	[19]
Pediatric lymphoma	DIS51BK2	Limited	Genetic Variation	[19]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Protein sel-1 homolog 1 (SEL1L) decreases the response to substance of Camptothecin.	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein sel-1 homolog 1 (SEL1L).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein sel-1 homolog 1 (SEL1L).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein sel-1 homolog 1 (SEL1L).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein sel-1 homolog 1 (SEL1L).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein sel-1 homolog 1 (SEL1L).	[26]
Vorinostat	DMWMPD4	Approved	Vorinostat affects the expression of Protein sel-1 homolog 1 (SEL1L).	[27]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein sel-1 homolog 1 (SEL1L).	[28]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Protein sel-1 homolog 1 (SEL1L).	[30]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Protein sel-1 homolog 1 (SEL1L).	[31]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein sel-1 homolog 1 (SEL1L).	[32]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein sel-1 homolog 1 (SEL1L).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein sel-1 homolog 1 (SEL1L).	[34]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Protein sel-1 homolog 1 (SEL1L).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein sel-1 homolog 1 (SEL1L).	[36]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein sel-1 homolog 1 (SEL1L).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	Marinol decreases the methylation of Protein sel-1 homolog 1 (SEL1L).	[29]

References

• [1] SEL1L and squamous cell carcinoma of the esophagus.Clin Cancer Res. 2004 Sep 1;10(17):5857-61. doi: 10.1158/1078-0432.CCR-04-0075.
• [2] Ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) prevents cell death in a cellular model of Parkinson's disease.Biochem Biophys Res Commun. 2018 Nov 30;506(3):516-521. doi: 10.1016/j.bbrc.2018.10.094. Epub 2018 Oct 22.
• [3] Endoplasmic reticulum quality control in cancer: Friend or foe.Semin Cancer Biol. 2015 Aug;33:25-33. doi: 10.1016/j.semcancer.2015.02.003. Epub 2015 Mar 18.
• [4] A single-nucleotide polymorphism in tumor suppressor gene SEL1L as a predictive and prognostic marker for pancreatic ductal adenocarcinoma in Caucasians.Mol Carcinog. 2012 May;51(5):433-8. doi: 10.1002/mc.20808. Epub 2011 Jun 7.
• [5] SEL1L SNP rs12435998, a predictor of glioblastoma survival and response to radio-chemotherapy.Oncotarget. 2015 May 20;6(14):12452-67. doi: 10.18632/oncotarget.3611.
• [6] Protein profile changes in the human breast cancer cell line MCF-7 in response to SEL1L gene induction.Proteomics. 2005 Jun;5(9):2433-42. doi: 10.1002/pmic.200401283.
• [7] SEL1L expression decreases breast tumor cell aggressiveness in vivo and in vitro.Cancer Res. 2002 Jan 15;62(2):567-74.
• [8] Mice deficient for ERAD machinery component Sel1L develop central diabetes insipidus.J Clin Invest. 2017 Oct 2;127(10):3591-3593. doi: 10.1172/JCI96839. Epub 2017 Sep 18.
• [9] A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery.PLoS Genet. 2012;8(6):e1002759. doi: 10.1371/journal.pgen.1002759. Epub 2012 Jun 14.
• [10] Protein Expression Analysis in Uterine Cervical Cancer for Potential Targets in Treatment.Pathol Oncol Res. 2019 Apr;25(2):493-501. doi: 10.1007/s12253-018-0401-0. Epub 2018 Mar 12.
• [11] A novel polymorphism in SEL1L confers susceptibility to Alzheimer's disease.Neurosci Lett. 2006 May 1;398(1-2):53-8. doi: 10.1016/j.neulet.2005.12.038. Epub 2006 Jan 10.
• [12] Down-modulation of SEL1L, an unfolded protein response and endoplasmic reticulum-associated degradation protein, sensitizes glioma stem cells to the cytotoxic effect of valproic acid.J Biol Chem. 2014 Jan 31;289(5):2826-38. doi: 10.1074/jbc.M113.527754. Epub 2013 Dec 5.
• [13] SEL1L microsatellite polymorphism in Japanese patients with autoimmune thyroid diseases.Thyroid. 2001 Apr;11(4):335-8. doi: 10.1089/10507250152039064.
• [14] Role of the endoplasmic reticulum-associated degradation (ERAD) pathway in degradation of hepatitis C virus envelope proteins and production of virus particles.J Biol Chem. 2011 Oct 28;286(43):37264-73. doi: 10.1074/jbc.M111.259085. Epub 2011 Aug 30.
• [15] SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo.Oncogene. 2003 Sep 25;22(41):6359-68. doi: 10.1038/sj.onc.1206665.
• [16] Putative tumor suppressor gene SEL1L was downregulated by aberrantly upregulated hsa-mir-155 in human pancreatic ductal adenocarcinoma.Mol Carcinog. 2014 Sep;53(9):711-21. doi: 10.1002/mc.22023. Epub 2013 May 9.
• [17] SEL1L expression in non-small cell lung cancer.Hum Pathol. 2006 May;37(5):505-12. doi: 10.1016/j.humpath.2005.12.012. Epub 2006 Mar 20.
• [18] Hypothalamic ER-associated degradation regulates POMC maturation, feeding, and age-associated obesity.J Clin Invest. 2018 Mar 1;128(3):1125-1140. doi: 10.1172/JCI96420. Epub 2018 Feb 19.
• [19] Notch signal transduction is not regulated by SEL1L in leukaemia and lymphoma cells in culture.Anticancer Res. 2002 Nov-Dec;22(6C):4211-4.
• [20] Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are characterised by differential activation of ER stress pathways: focus on UPR target genes.Cell Stress Chaperones. 2018 Sep;23(5):897-912. doi: 10.1007/s12192-018-0897-y. Epub 2018 May 4.
• [21] Melatonin reduces endoplasmic reticulum stress and corneal dystrophy-associated TGFBIp through activation of endoplasmic reticulum-associated protein degradation.J Pineal Res. 2017 Oct;63(3). doi: 10.1111/jpi.12426. Epub 2017 Jul 18.
• [22] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [23] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [24] 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.
• [25] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [26] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [27] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [28] 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.
• [29] Epigenetic activation of O-linked -N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia. EBioMedicine. 2020 Apr;54:102678. doi: 10.1016/j.ebiom.2020.102678. Epub 2020 Apr 6.
• [30] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [31] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [32] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [33] 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.
• [34] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [35] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [36] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [37] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [38] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.