Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL89HGW)

• DOT Name: SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1)
• Synonyms: srGAP1; Rho GTPase-activating protein 13
• Gene Name: SRGAP1
• Related Disease:
  Rheumatoid arthritis
  Renal dysplasia
  Thyroid gland papillary carcinoma
  Congenital anomaly of kidney and urinary tract
  Epithelial ovarian cancer
  Adult glioblastoma
  Glioblastoma multiforme
  Intellectual disability
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Thyroid cancer, nonmedullary, 2
• UniProt ID: SRGP1_HUMAN
• Pfam ID: PF00611 ; PF00620 ; PF00018
• Sequence:
  MSTPSRFKKDKEIIAEYESQVKEIRAQLVEQQKCLEQQTEMRVQLLQDLQDFFRKKAEIE
  TEYSRNLEKLAERFMAKTRSTKDHQQYKKDQNLLSPVNCWYLLLNQVRRESKDHATLSDI
  YLNNVIMRFMQISEDSTRMFKKSKEIAFQLHEDLMKVLNELYTVMKTYHMYHAESISAES
  KLKEAEKQEEKQIGRSGDPVFHIRLEERHQRRSSVKKIEKMKEKRQAKYSENKLKSIKAR
  NEYLLTLEATNASVFKYYIHDLSDLIDCCDLGYHASLNRALRTYLSAEYNLETSRHEGLD
  IIENAVDNLEPRSDKQRFMEMYPAAFCPPMKFEFQSHMGDEVCQVSAQQPVQAELMLRYQ
  QLQSRLATLKIENEEVKKTTEATLQTIQDMVTIEDYDVSECFQHSRSTESVKSTVSETYL
  SKPSIAKRRANQQETEQFYFMKLREYLEGSNLITKLQAKHDLLQRTLGEGHRAEYMTTRP
  PNVPPKPQKHRKSRPRSQYNTKLFNGDLETFVKDSGQVIPLIVESCIRFINLYGLQHQGI
  FRVSGSQVEVNDIKNSFERGENPLADDQSNHDINSVAGVLKLYFRGLENPLFPKERFNDL
  ISCIRIDNLYERALHIRKLLLTLPRSVLIVMRYLFAFLNHLSQYSDENMMDPYNLAICFG
  PTLMPVPEIQDQVSCQAHVNEIIKTIIIHHETIFPDAKELDGPVYEKCMAGDDYCDSPYS
  EHGTLEEVDQDAGTEPHTSEDECEPIEAIAKFDYVGRSARELSFKKGASLLLYHRASEDW
  WEGRHNGIDGLVPHQYIVVQDMDDTFSDTLSQKADSEASSGPVTEDKSSSKDMNSPTDRH
  PDGYLARQRKRGEPPPPVRRPGRTSDGHCPLHPPHALSNSSVDLGSPSLASHPRGLLQNR
  GLNNDSPERRRRPGHGSLTNISRHDSLKKIDSPPIRRSTSSGQYTGFNDHKPLDPETIAQ
  DIEETMNTALNELRELERQSTAKHAPDVVLDTLEQVKNSPTPATSTESLSPLHNVALRSS
  EPQIRRSTSSSSDTMSTFKPMVAPRMGVQLKPPALRPKPAVLPKTNPTIGPAPPPQGPTD
  KSCTM
• Function: GTPase-activating protein for RhoA and Cdc42 small GTPases. Together with CDC42 seems to be involved in the pathway mediating the repulsive signaling of Robo and Slit proteins in neuronal migration. SLIT2, probably through interaction with ROBO1, increases the interaction of SRGAP1 with ROBO1 and inactivates CDC42.
• Tissue Specificity: Expressed in brain, lung, kidney, and testis.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  Inactivation of CDC42 and RAC1 (R-HSA-428543)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Definitive	Genetic Variation	[1]
Renal dysplasia	DIS3DFGD	Strong	Genetic Variation	[2]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[3]
Congenital anomaly of kidney and urinary tract	DIS84IVH	moderate	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Disputed	Genetic Variation	[4]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[5]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[5]
Intellectual disability	DISMBNXP	Limited	Biomarker	[6]
Thyroid cancer	DIS3VLDH	Limited	Genetic Variation	[7]
Thyroid gland carcinoma	DISMNGZ0	Limited	Genetic Variation	[7]
Thyroid tumor	DISLVKMD	Limited	Genetic Variation	[7]
Thyroid cancer, nonmedullary, 2	DISJ3RYM	No Known	Autosomal dominant	[3]

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 SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[17]
Marinol	DM70IK5	Approved	Marinol increases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[18]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of SLIT-ROBO Rho GTPase-activating protein 1 (SRGAP1).	[22]

References

• [1] Association of CD8(+) T-cells with bone erosion in patients with rheumatoid arthritis.Int J Rheum Dis. 2018 Feb;21(2):440-446. doi: 10.1111/1756-185X.13090. Epub 2017 May 16.
• [2] Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract.Hum Genet. 2015 Aug;134(8):905-16. doi: 10.1007/s00439-015-1570-5. Epub 2015 May 31.
• [3] SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility. J Clin Endocrinol Metab. 2013 May;98(5):E973-80. doi: 10.1210/jc.2012-3823. Epub 2013 Mar 28.
• [4] Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women.Nat Commun. 2014 Aug 19;5:4682. doi: 10.1038/ncomms5682.
• [5] MicroRNA-145 Promotes the Phenotype of Human Glioblastoma Cells Selected for Invasion.Anticancer Res. 2015 Jun;35(6):3209-15.
• [6] The inverse F-BAR domain protein srGAP2 acts through srGAP3 to modulate neuronal differentiation and neurite outgrowth of mouse neuroblastoma cells.PLoS One. 2013;8(3):e57865. doi: 10.1371/journal.pone.0057865. Epub 2013 Mar 7.
• [7] HABP2 germline variants are uncommon in familial nonmedullary thyroid cancer.BMC Med Genet. 2016 Aug 17;17(1):60. doi: 10.1186/s12881-016-0323-1.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [15] 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.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [18] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [19] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.