Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKX7P8G)

• DOT Name: Sprouty-related, EVH1 domain-containing protein 1 (SPRED1)
• Synonyms: Spred-1; hSpred1
• Gene Name: SPRED1
• Related Disease:
  Acute myelogenous leukaemia
  Legius syndrome
  Breast cancer
  Breast carcinoma
  Capillary malformation-arteriovenous malformation syndrome
  Cowden disease
  Hepatocellular carcinoma
  Megalencephaly
  Neoplasm
  Noonan syndrome
  Plexiform neurofibroma
  Psoriasis
  Leukemia
  Type-1/2 diabetes
  Advanced cancer
  Congenital nervous system disorder
  Melanoma
  Myeloproliferative neoplasm
  Prostate cancer
  Prostate carcinoma
  Watson syndrome
• UniProt ID: SPRE1_HUMAN
• PDB ID: 3SYX; 6V65; 6V6F
• Pfam ID: PF05210 ; PF00568
• Sequence:
  MSEETATSDNDNSYARVRAVVMTRDDSSGGWLPLGGSGLSSVTVFKVPHQEENGCADFFI
  RGERLRDKMVVLECMLKKDLIYNKVTPTFHHWKIDDKKFGLTFQSPADARAFDRGIRRAI
  EDISQGCPESKNEAEGADDLQANEEDSSSSLVKDHLFQQETVVTSEPYRSSNIRPSPFED
  LNARRVYMQSQANQITFGQPGLDIQSRSMEYVQRQISKECGSLKSQNRVPLKSIRHVSFQ
  DEDEIVRINPRDILIRRYADYRHPDMWKNDLERDDADSSIQFSKPDSKKSDYLYSCGDET
  KLSSPKDSVVFKTQPSSLKIKKSKRRKEDGERSRCVYCQERFNHEENVRGKCQDAPDPIK
  RCIYQVSCMLCAESMLYHCMSDSEGDFSDPCSCDTSDDKFCLRWLALVALSFIVPCMCCY
  VPLRMCHRCGEACGCCGGKHKAAG
• Function: Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase. Negatively regulates hematopoiesis of bone marrow. Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2. Attenuates actin stress fiber formation via inhibition of TESK1-mediated phosphorylation of cofilin. Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells.
• Tissue Specificity: Weakly expressed in embryonic cell line HEK293.
• Reactome Pathway:
  FGFRL1 modulation of FGFR1 signaling (R-HSA-5658623)
  RAS signaling downstream of NF1 loss-of-function variants (R-HSA-6802953)
  Regulation of RAS by GAPs (R-HSA-5658442)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Posttranslational Modification	[1]
Legius syndrome	DISO9AOZ	Definitive	Autosomal dominant	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Strong	Biomarker	[4]
Cowden disease	DISMYKCE	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Megalencephaly	DISYW5SV	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Noonan syndrome	DIS7Q7DN	Strong	Genetic Variation	[4]
Plexiform neurofibroma	DISW4XX7	Strong	Genetic Variation	[8]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[9]
Leukemia	DISNAKFL	moderate	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[12]
Congenital nervous system disorder	DIS2BIP8	Limited	Biomarker	[13]
Melanoma	DIS1RRCY	Limited	Biomarker	[12]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Genetic Variation	[14]
Prostate cancer	DISF190Y	Limited	Altered Expression	[15]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[15]
Watson syndrome	DIS8ZGU7	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[21]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[23]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[24]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[25]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[29]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[33]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[34]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Sprouty-related, EVH1 domain-containing protein 1 (SPRED1).	[35]

References

• [1] A Pilot Study of Aberrant CpG Island Hypermethylation of SPRED1 in Acute Myeloloid Leukemia.Int J Med Sci. 2019 Jan 1;16(2):324-330. doi: 10.7150/ijms.27757. eCollection 2019.
• [2] 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.
• [3] Estrogen-induced miR-196a elevation promotes tumor growth and metastasis via targeting SPRED1 in breast cancer.Mol Cancer. 2018 Apr 23;17(1):83. doi: 10.1186/s12943-018-0830-0.
• [4] A review of craniofacial and dental findings of the RASopathies.Orthod Craniofac Res. 2017 Jun;20 Suppl 1(Suppl 1):32-38. doi: 10.1111/ocr.12144.
• [5] Familial multiple lipomatosis with clear autosomal dominant inheritance and onset in early adolescence.BMJ Case Rep. 2011 Feb 17;2011:bcr1020103395. doi: 10.1136/bcr.10.2010.3395.
• [6] Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors.Oncogene. 2006 Oct 5;25(45):6056-66. doi: 10.1038/sj.onc.1209635. Epub 2006 May 1.
• [7] Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1.J Biol Chem. 2016 Feb 12;291(7):3124-34. doi: 10.1074/jbc.M115.703710. Epub 2015 Dec 3.
• [8] Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome.JAMA. 2009 Nov 18;302(19):2111-8. doi: 10.1001/jama.2009.1663.
• [9] Multi-omics study in monozygotic twins confirm the contribution of de novo mutation to psoriasis.J Autoimmun. 2020 Jan;106:102349. doi: 10.1016/j.jaut.2019.102349. Epub 2019 Oct 16.
• [10] SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia.Oncogene. 2015 Jan 29;34(5):631-8. doi: 10.1038/onc.2013.587. Epub 2014 Jan 27.
• [11] Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1.J Mol Cell Cardiol. 2012 Jul;53(1):64-72. doi: 10.1016/j.yjmcc.2012.04.003. Epub 2012 Apr 16.
• [12] Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma.Science. 2018 Nov 30;362(6418):1055-1060. doi: 10.1126/science.aau6509. Epub 2018 Nov 1.
• [13] Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007 Sep;39(9):1120-6. doi: 10.1038/ng2113. Epub 2007 Aug 19.
• [14] Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress.Cell Stem Cell. 2018 May 3;22(5):713-725.e8. doi: 10.1016/j.stem.2018.04.002. Epub 2018 Apr 26.
• [15] Evidence for downregulation of the negative regulator SPRED2 in clinical prostate cancer.Br J Cancer. 2013 Feb 19;108(3):597-601. doi: 10.1038/bjc.2012.507. Epub 2012 Nov 20.
• [16] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [17] 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.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] 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.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [22] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [23] 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.
• [24] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [27] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] 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.
• [30] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [31] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [32] Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation. J Clin Med. 2020 Feb 3;9(2):405. doi: 10.3390/jcm9020405.
• [33] 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.
• [34] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [35] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.