Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUTPVA9)

• DOT Name: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1)
• Synonyms: P-Rex1; PtdIns(3,4,5)-dependent Rac exchanger 1
• Gene Name: PREX1
• Related Disease:
  Acrodysostosis
  Acute myelogenous leukaemia
  Adult glioblastoma
  Advanced cancer
  Autism
  Breast neoplasm
  Cardiovascular disease
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal adenoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Glioblastoma multiforme
  Neoplasm
  Non-insulin dependent diabetes
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Primary cutaneous T-cell lymphoma
  Cutaneous melanoma
  Melanoma
• UniProt ID: PREX1_HUMAN
• PDB ID: 3QIK; 4YON; 5D27; 5D3V; 5D3W; 5D3X; 5D3Y; 5FI0; 5FI1; 6PCV; 6VSK; 7RX9
• Pfam ID: PF00610 ; PF00621
• Sequence:
  MEAPSGSEPGGDGAGDCAHPDPRAPGAAAPSSGPGPCAAARESERQLRLRLCVLNEILGT
  ERDYVGTLRFLQSAFLHRIRQNVADSVEKGLTEENVKVLFSNIEDILEVHKDFLAALEYC
  LHPEPQSQHELGNVFLKFKDKFCVYEEYCSNHEKALRLLVELNKIPTVRAFLLSCMLLGG
  RKTTDIPLEGYLLSPIQRICKYPLLLKELAKRTPGKHPDHPAVQSALQAMKTVCSNINET
  KRQMEKLEALEQLQSHIEGWEGSNLTDICTQLLLQGTLLKISAGNIQERAFFLFDNLLVY
  CKRKSRVTGSKKSTKRTKSINGSLYIFRGRINTEVMEVENVEDGTADYHSNGYTVTNGWK
  IHNTAKNKWFVCMAKTAEEKQKWLDAIIREREQRESLKLGMERDAYVMIAEKGEKLYHMM
  MNKKVNLIKDRRRKLSTVPKCFLGNEFVAWLLEIGEISKTEEGVNLGQALLENGIIHHVS
  DKHQFKNEQVMYRFRYDDGTYKARSELEDIMSKGVRLYCRLHSLYTPVIKDRDYHLKTYK
  SVLPGSKLVDWLLAQGDCQTREEAVALGVGLCNNGFMHHVLEKSEFRDESQYFRFHADEE
  MEGTSSKNKQLRNDFKLVENILAKRLLILPQEEDYGFDIEEKNKAVVVKSVQRGSLAEVA
  GLQVGRKIYSINEDLVFLRPFSEVESILNQSFCSRRPLRLLVATKAKEIIKIPDQPDTLC
  FQIRGAAPPYVYAVGRGSEAMAAGLCAGQCILKVNGSNVMNDGAPEVLEHFQAFRSRREE
  ALGLYQWIYHTHEDAQEARASQEASTEDPSGEQAQEEDQADSAFPLLSLGPRLSLCEDSP
  MVTLTVDNVHLEHGVVYEYVSTAGVRCHVLEKIVEPRGCFGLTAKILEAFAANDSVFVEN
  CRRLMALSSAIVTMPHFEFRNICDTKLESIGQRIACYQEFAAQLKSRVSPPFKQAPLEPH
  PLCGLDFCPTNCHINLMEVSYPKTTPSVGRSFSIRFGRKPSLIGLDPEQGHLNPMSYTQH
  CITTMAAPSWKCLPAAEGDPQGQGLHDGSFGPASGTLGQEDRGLSFLLKQEDREIQDAYL
  QLFTKLDVALKEMKQYVTQINRLLSTITEPTSGGSCDASLAEEASSLPLVSEESEMDRSD
  HGGIKKVCFKVAEEDQEDSGHDTMSYRDSYSECNSNRDSVLSYTSVRSNSSYLGSDEMGS
  GDELPCDMRIPSDKQDKLHGCLEHLFNQVDSINALLKGPVMSRAFEETKHFPMNHSLQEF
  KQKEECTIRGRSLIQISIQEDPWNLPNSIKTLVDNIQRYVEDGKNQLLLALLKCTDTELQ
  LRRDAIFCQALVAAVCTFSKQLLAALGYRYNNNGEYEESSRDASRKWLEQVAATGVLLHC
  QSLLSPATVKEERTMLEDIWVTLSELDNVTFSFKQLDENYVANTNVFYHIEGSRQALKVI
  FYLDSYHFSKLPSRLEGGASLRLHTALFTKVLENVEGLPSPGSQAAEDLQQDINAQSLEK
  VQQYYRKLRAFYLERSNLPTDASTTAVKIDQLIRPINALDELCRLMKSFVHPKPGAAGSV
  GAGLIPISSELCYRLGACQMVMCGTGMQRSTLSVSLEQAAILARSHGLLPKCIMQATDIM
  RKQGPRVEILAKNLRVKDQMPQGAPRLYRLCQPPVDGDL
• Function: Functions as a RAC guanine nucleotide exchange factor (GEF), which activates the Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. May function downstream of heterotrimeric G proteins in neutrophils.
• Tissue Specificity: Mainly expressed in peripheral blood leukocytes and brain. Expressed at intermediate level in spleen and lymph nodes, and weakly expressed in other tissues.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOG GTPase cycle (R-HSA-9013408)
  RHOJ GTPase cycle (R-HSA-9013409)
  RAC3 GTPase cycle (R-HSA-9013423)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acrodysostosis	DISSV94Z	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Autism	DISV4V1Z	Strong	Genetic Variation	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[7]
Colon cancer	DISVC52G	Strong	Genetic Variation	[8]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[8]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[9]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[8]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[8]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[11]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[4]
Prostate cancer	DISF190Y	Strong	Altered Expression	[12]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[12]
Primary cutaneous T-cell lymphoma	DIS35WVW	Disputed	Biomarker	[13]
Cutaneous melanoma	DIS3MMH9	Limited	Biomarker	[14]
Melanoma	DIS1RRCY	Limited	Biomarker	[14]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1) affects the response to substance of DTI-015.	[32]
Permethrin	DMZ0Q1G	Approved	Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1) affects the response to substance of Permethrin.	[33]

17 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 Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[21]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[23]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[24]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[25]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[26]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[30]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1).	[31]

References

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• [2] Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras.Cell. 2017 Feb 23;168(5):890-903.e15. doi: 10.1016/j.cell.2017.01.013. Epub 2017 Feb 2.
• [3] Zeb1 potentiates genome-wide gene transcription with Lef1 to promote glioblastoma cell invasion.EMBO J. 2018 Aug 1;37(15):e97115. doi: 10.15252/embj.201797115. Epub 2018 Jun 14.
• [4] Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance: a genome-wide genetic interaction study.Mol Med. 2018 Jun 11;24(1):30. doi: 10.1186/s10020-018-0031-8.
• [5] Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior.Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):E6964-72. doi: 10.1073/pnas.1512913112. Epub 2015 Nov 30.
• [6] Rac signaling in breast cancer: a tale of GEFs and GAPs.Cell Signal. 2012 Feb;24(2):353-362. doi: 10.1016/j.cellsig.2011.08.011. Epub 2011 Aug 27.
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• [9] Discovery of common and rare genetic risk variants for colorectal cancer.Nat Genet. 2019 Jan;51(1):76-87. doi: 10.1038/s41588-018-0286-6. Epub 2018 Dec 3.
• [10] PREX1 drives spontaneous bone dissemination of ER+ breast cancer cells.Oncogene. 2020 Feb;39(6):1318-1334. doi: 10.1038/s41388-019-1064-3. Epub 2019 Oct 21.
• [11] Analysis of candidate genes on chromosome 20q12-13.1 reveals evidence for BMI mediated association of PREX1 with type 2 diabetes in European Americans.Genomics. 2010 Oct;96(4):211-9. doi: 10.1016/j.ygeno.2010.07.006. Epub 2010 Jul 30.
• [12] Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis.Oncogene. 2009 Apr 23;28(16):1853-63. doi: 10.1038/onc.2009.30. Epub 2009 Mar 23.
• [13] TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL.Blood. 2017 Aug 24;130(8):982-994. doi: 10.1182/blood-2017-03-770982. Epub 2017 Jul 10.
• [14] P-REX1 amplification promotes progression of cutaneous melanoma via the PAK1/P38/MMP-2 pathway.Cancer Lett. 2017 Oct 28;407:66-75. doi: 10.1016/j.canlet.2017.08.001. Epub 2017 Aug 10.
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• [17] 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.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [22] Prenatal arsenic exposure and the epigenome: altered microRNAs associated with innate and adaptive immune signaling in newborn cord blood. Environ Mol Mutagen. 2014 Apr;55(3):196-208. doi: 10.1002/em.21842. Epub 2013 Dec 10.
• [23] 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.
• [24] 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.
• [25] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [26] 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.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [29] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [30] 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.
• [31] Imbalance in the antioxidant defence system and pro-genotoxic status induced by high glucose concentrations: In vitro testing in human liver cells. Toxicol In Vitro. 2020 Dec;69:105001. doi: 10.1016/j.tiv.2020.105001. Epub 2020 Sep 15.
• [32] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [33] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.