Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1QQ7FR)

• DOT Name: SLIT and NTRK-like protein 1 (SLITRK1)
• Synonyms: Leucine-rich repeat-containing protein 12
• Gene Name: SLITRK1
• Related Disease:
  Attention deficit hyperactivity disorder
  Neoplasm
  Cardiac arrest
  Mental disorder
  Myoclonic dystonia 11
  Schizophrenia
  Advanced cancer
  Chromosomal disorder
  Melanoma
  Obsessive compulsive disorder
  Tourette syndrome
  Trichotillomania
• UniProt ID: SLIK1_HUMAN
• PDB ID: 4RCA; 4RCW
• Pfam ID: PF13855
• Sequence:
  MLLWILLLETSLCFAAGNVTGDVCKEKICSCNEIEGDLHVDCEKKGFTSLQRFTAPTSQF
  YHLFLHGNSLTRLFPNEFANFYNAVSLHMENNGLHEIVPGAFLGLQLVKRLHINNNKIKS
  FRKQTFLGLDDLEYLQADFNLLRDIDPGAFQDLNKLEVLILNDNLISTLPANVFQYVPIT
  HLDLRGNRLKTLPYEEVLEQIPGIAEILLEDNPWDCTCDLLSLKEWLENIPKNALIGRVV
  CEAPTRLQGKDLNETTEQDLCPLKNRVDSSLPAPPAQEETFAPGPLPTPFKTNGQEDHAT
  PGSAPNGGTKIPGNWQIKIRPTAAIATGSSRNKPLANSLPCPGGCSCDHIPGSGLKMNCN
  NRNVSSLADLKPKLSNVQELFLRDNKIHSIRKSHFVDYKNLILLDLGNNNIATVENNTFK
  NLLDLRWLYMDSNYLDTLSREKFAGLQNLEYLNVEYNAIQLILPGTFNAMPKLRILILNN
  NLLRSLPVDVFAGVSLSKLSLHNNYFMYLPVAGVLDQLTSIIQIDLHGNPWECSCTIVPF
  KQWAERLGSEVLMSDLKCETPVNFFRKDFMLLSNDEICPQLYARISPTLTSHSKNSTGLA
  ETGTHSNSYLDTSRVSISVLVPGLLLVFVTSAFTVVGMLVFILRNRKRSKRRDANSSASE
  INSLQTVCDSSYWHNGPYNADGAHRVYDCGSHSLSD
• Function: It is involved in synaptogenesis and promotes excitatory synapse differentiation. Enhances neuronal dendrite outgrowth.
• Tissue Specificity: Expressed predominantly in the frontal lobe of the cerebral cortex of the brain. Also expressed in some astrocytic brain tumors such as astrocytomas, oligodendrogliomas, glioblastomas, gangliogliomas and primitive neuroectodermal tumors.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway: Receptor-type tyrosine-protein phosphatases (R-HSA-388844)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[2]
Cardiac arrest	DIS9DIA4	Strong	Biomarker	[3]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[4]
Myoclonic dystonia 11	DISMVAWP	Strong	Genetic Variation	[5]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]
Chromosomal disorder	DISM5BB5	Limited	Genetic Variation	[8]
Melanoma	DIS1RRCY	Limited	Biomarker	[7]
Obsessive compulsive disorder	DIS1ZMM2	Limited	Genetic Variation	[9]
Tourette syndrome	DISX9D54	Limited	Autosomal dominant	[10]
Trichotillomania	DISDI464	Limited	Unknown	[11]

8 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 SLIT and NTRK-like protein 1 (SLITRK1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SLIT and NTRK-like protein 1 (SLITRK1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SLIT and NTRK-like protein 1 (SLITRK1).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of SLIT and NTRK-like protein 1 (SLITRK1).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of SLIT and NTRK-like protein 1 (SLITRK1).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of SLIT and NTRK-like protein 1 (SLITRK1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SLIT and NTRK-like protein 1 (SLITRK1).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of SLIT and NTRK-like protein 1 (SLITRK1).	[20]

2 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 SLIT and NTRK-like protein 1 (SLITRK1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of SLIT and NTRK-like protein 1 (SLITRK1).	[18]

References

• [1] SLITRK1 binds 14-3-3 and regulates neurite outgrowth in a phosphorylation-dependent manner.Biol Psychiatry. 2009 Nov 15;66(10):918-25. doi: 10.1016/j.biopsych.2009.05.033. Epub 2009 Jul 29.
• [2] ZAP-70 expression and proliferative activity in chronic lymphocytic leukemia.Leuk Lymphoma. 2013 Jun;54(6):1171-6. doi: 10.3109/10428194.2012.742527. Epub 2012 Nov 19.
• [3] Multimodal Outcome Prognostication After Cardiac Arrest and Targeted Temperature Management: Analysis at 36C.Neurocrit Care. 2018 Feb;28(1):104-109. doi: 10.1007/s12028-017-0393-8.
• [4] Characterization of SLITRK1 variation in obsessive-compulsive disorder.PLoS One. 2013 Aug 21;8(8):e70376. doi: 10.1371/journal.pone.0070376. eCollection 2013.
• [5] Autosomal dominant myoclonus-dystonia and Tourette syndrome in a family without linkage to the SGCE gene.Mov Disord. 2007 Oct 31;22(14):2090-6. doi: 10.1002/mds.21674.
• [6] Genome-wide association study results for educational attainment aid in identifying genetic heterogeneity of schizophrenia.Nat Commun. 2018 Aug 6;9(1):3078. doi: 10.1038/s41467-018-05510-z.
• [7] Copper Chelation Inhibits BRAF(V600E)-Driven Melanomagenesis and Counters Resistance to BRAF(V600E) and MEK1/2 Inhibitors.Cancer Res. 2017 Nov 15;77(22):6240-6252. doi: 10.1158/0008-5472.CAN-16-1190. Epub 2017 Oct 6.
• [8] The genetic basis of Gilles de la Tourette Syndrome.Neurosci Biobehav Rev. 2013 Jul;37(6):1026-39. doi: 10.1016/j.neubiorev.2013.01.016. Epub 2013 Jan 17.
• [9] Gene variations in PBX1, LMX1A and SLITRK1 are associated with obsessive-compulsive disorder and its clinical features.J Clin Neurosci. 2019 Mar;61:180-185. doi: 10.1016/j.jocn.2018.10.042. Epub 2018 Oct 28.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] SLITRK1 mutations in trichotillomania. Mol Psychiatry. 2006 Oct;11(10):887-9. doi: 10.1038/sj.mp.4001898.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.