Details of Drug Off-Target (DOT)

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

• DOT Name: Rho guanine nucleotide exchange factor TIAM1 (TIAM1)
• Synonyms: T-lymphoma invasion and metastasis-inducing protein 1; TIAM-1
• Gene Name: TIAM1
• Related Disease: Neurodevelopmental disorder with language delay and seizures
• UniProt ID: TIAM1_HUMAN
• PDB ID: 2D8I; 3KZD; 3KZE; 4GVC; 4GVD; 4K2O; 4K2P; 4NXP; 4NXQ; 4NXR
• Pfam ID: PF00595 ; PF00169 ; PF02196 ; PF00621 ; PF18385
• Sequence:
  MGNAESQHVEHEFYGEKHASLGRKHTSRSLRLSHKTRRTRHASSGKVIHRNSEVSTRSSS
  TPSIPQSLAENGLEPFSQDGTLEDFGSPIWVDRVDMGLRPVSYTDSSVTPSVDSSIVLTA
  ASVQSMPDTEESRLYGDDATYLAEGGRRQHSYTSNGPTFMETASFKKKRSKSADIWREDS
  LEFSLSDLSQEHLTSNEEILGSAEEKDCEEARGMETRASPRQLSTCQRANSLGDLYAQKN
  SGVTANGGPGSKFAGYCRNLVSDIPNLANHKMPPAAAEETPPYSNYNTLPCRKSHCLSEG
  ATNPQISHSNSMQGRRAKTTQDVNAGEGSEFADSGIEGATTDTDLLSRRSNATNSSYSPT
  TGRAFVGSDSGSSSTGDAARQGVYENFRRELEMSTTNSESLEEAGSAHSDEQSSGTLSSP
  GQSDILLTAAQGTVRKAGALAVKNFLVHKKNKKVESATRRKWKHYWVSLKGCTLFFYESD
  GRSGIDHNSIPKHAVWVENSIVQAVPEHPKKDFVFCLSNSLGDAFLFQTTSQTELENWIT
  AIHSACATAVARHHHKEDTLRLLKSEIKKLEQKIDMDEKMKKMGEMQLSSVTDSKKKKTI
  LDQIFVWEQNLEQFQMDLFRFRCYLASLQGGELPNPKRLLAFASRPTKVAMGRLGIFSVS
  SFHALVAARTGETGVRRRTQAMSRSASKRRSRFSSLWGLDTTSKKKQGRPSINQVFGEGT
  EAVKKSLEGIFDDIVPDGKREKEVVLPNVHQHNPDCDIWVHEYFTPSWFCLPNNQPALTV
  VRPGDTARDTLELICKTHQLDHSAHYLRLKFLIENKMQLYVPQPEEDIYELLYKEIEICP
  KVTQSIHIEKSDTAADTYGFSLSSVEEDGIRRLYVNSVKETGLASKKGLKAGDEILEINN
  RAADALNSSMLKDFLSQPSLGLLVRTYPELEEGVELLESPPHRVDGPADLGESPLAFLTS
  NPGHSLCSEQGSSAETAPEETEGPDLESSDETDHSSKSTEQVAAFCRSLHEMNPSDQSPS
  PQDSTGPQLATMRQLSDADKLRKVICELLETERTYVKDLNCLMERYLKPLQKETFLTQDE
  LDVLFGNLTEMVEFQVEFLKTLEDGVRLVPDLEKLEKVDQFKKVLFSLGGSFLYYADRFK
  LYSAFCASHTKVPKVLVKAKTDTAFKAFLDAQNPKQQHSSTLESYLIKPIQRILKYPLLL
  RELFALTDAESEEHYHLDVAIKTMNKVASHINEMQKIHEEFGAVFDQLIAEQTGEKKEVA
  DLSMGDLLLHTTVIWLNPPASLGKWKKEPELAAFVFKTAVVLVYKDGSKQKKKLVGSHRL
  SIYEDWDPFRFRHMIPTEALQVRALASADAEANAVCEIVHVKSESEGRPERVFHLCCSSP
  ESRKDFLKAVHSILRDKHRRQLLKTESLPSSQQYVPFGGKRLCALKGARPAMSRAVSAPS
  KSLGRRRRRLARNRFTIDSDAVSASSPEKESQQPPGGGDTDRWVEEQFDLAQYEEQDDIK
  ETDILSDDDEFCESVKGASVDRDLQERLQATSISQRERGRKTLDSHASRMAQLKKQAALS
  GINGGLESASEEVIWVRREDFAPSRKLNTEI
• Function: Guanyl-nucleotide exchange factor that activates RHO-like proteins and connects extracellular signals to cytoskeletal activities. Activates RAC1, CDC42, and to a lesser extent RHOA and their downstream signaling to regulate processes like cell adhesion and cell migration.
• Tissue Specificity: Found in virtually all analyzed tumor cell lines including B- and T-lymphomas, neuroblastomas, melanomas and carcinomas.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  cAMP sig.ling pathway (hsa04024)
  Chemokine sig.ling pathway (hsa04062)
  Tight junction (hsa04530)
  Regulation of actin cytoskeleton (hsa04810)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  EPHB-mediated forward signaling (R-HSA-3928662)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RAC3 GTPase cycle (R-HSA-9013423)
  Activated NTRK2 signals through CDK5 (R-HSA-9032845)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with language delay and seizures	DISA0NNO	Strong	Autosomal recessive	[1]

3 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 Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[2]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[15]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[16]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Rho guanine nucleotide exchange factor TIAM1 (TIAM1).	[17]

References

• [1] Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet. 2017 Apr;49(4):504-510. doi: 10.1038/ng.3789. Epub 2017 Feb 13.
• [2] 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.
• [3] Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. Toxicol In Vitro. 2015 Sep;29(6):1231-9. doi: 10.1016/j.tiv.2014.10.012. Epub 2014 Oct 24.
• [4] 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.
• [5] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [6] 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.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] 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.
• [10] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [11] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [12] 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.
• [13] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [17] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.