Details of Drug Off-Target (DOT)

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

• DOT Name: Protein spire homolog 1 (SPIRE1)
• Synonyms: Spir-1
• Gene Name: SPIRE1
• Related Disease:
  Cardiovascular disease
  Stroke
• UniProt ID: SPIR1_HUMAN
• PDB ID: 2YLE; 2YLF; 3R7G; 3RBW
• Pfam ID: PF16474
• Sequence:
  MAQAAGPAGGGEPRTEAVGGEGPREPGAAGGAAGGSRDALSLEEILRLYNQPINEEQAWA
  VCYQCCGSLRAAARRRQPRHRVRSAAQIRVWRDGAVTLAPAADDAGEPPPVAGKLGYSQC
  METEVIESLGIIIYKALDYGLKENEERELSPPLEQLIDHMANTVEADGSNDEGYEAAEEG
  LGDEDEKRKISAIRSYRDVMKLCAAHLPTESDAPNHYQAVCRALFAETMELHTFLTKIKS
  AKENLKKIQEMEKSDESSTDLEELKNADWARFWVQVMRDLRNGVKLKKVQERQYNPLPIE
  YQLTPYEMLMDDIRCKRYTLRKVMVNGDIPPRLKKSAHEIILDFIRSRPPLNPVSARKLK
  PTPPRPRSLHERILEEIKAERKLRPVSPEEIRRSRLAMRPLSMSYSFDLSDVTTPESTKN
  LVESSMVNGGLTSQTKENGLSTSQQVPAQRKKLLRAPTLAELDSSESEEETLHKSTSSSS
  VSPSFPEEPVLEAVSTRKKPPKFLPISSTPQPERRQPPQRRHSIEKETPTNVRQFLPPSR
  QSSRSLEEFCYPVECLALTVEEVMHIRQVLVKAELEKYQQYKDIYTALKKGKLCFCCRTR
  RFSFFTWSYTCQFCKRPVCSQCCKKMRLPSKPYSTLPIFSLGPSALQRGESSMRSEKPST
  AHHRPLRSIARFSSKSKSMDKSDEELQFPKELMEDWSTMEVCVDCKKFISEIISSSRRSL
  VLANKRARLKRKTQSFYMSSPGPSEYCPSERTISEI
• Function: Acts as an actin nucleation factor, remains associated with the slow-growing pointed end of the new filament. Involved in intracellular vesicle transport along actin fibers, providing a novel link between actin cytoskeleton dynamics and intracellular transport. Required for asymmetric spindle positioning and asymmetric cell division during meiosis. Required for normal formation of the cleavage furrow and for polar body extrusion during female germ cell meiosis. Also acts in the nucleus: together with FMN2, promotes assembly of nuclear actin filaments in response to DNA damage in order to facilitate movement of chromatin and repair factors after DNA damage. In addition, promotes innate immune signaling downstream of dsRNA sensing. Mechanistically, contributes to IRF3 phosphorylation and activation downstream of MAVS and upstream of TBK1.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[1]
Stroke	DISX6UHX	Limited	Biomarker	[2]

14 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 spire homolog 1 (SPIRE1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein spire homolog 1 (SPIRE1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein spire homolog 1 (SPIRE1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein spire homolog 1 (SPIRE1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein spire homolog 1 (SPIRE1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein spire homolog 1 (SPIRE1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein spire homolog 1 (SPIRE1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein spire homolog 1 (SPIRE1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein spire homolog 1 (SPIRE1).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein spire homolog 1 (SPIRE1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein spire homolog 1 (SPIRE1).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein spire homolog 1 (SPIRE1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein spire homolog 1 (SPIRE1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein spire homolog 1 (SPIRE1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein spire homolog 1 (SPIRE1).	[16]

References

• [1] PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease.Cochrane Database Syst Rev. 2017 Apr 28;4(4):CD011748. doi: 10.1002/14651858.CD011748.pub2.
• [2] Cholesterol and stroke: Roll of PCSK9 inhibitors.Neurologia (Engl Ed). 2019 Apr;34(3):198-203. doi: 10.1016/j.nrl.2017.03.009. Epub 2017 May 24.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] 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.
• [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.