Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHGNC0A)

• DOT Name: Rho guanine nucleotide exchange factor 3 (ARHGEF3)
• Synonyms: Exchange factor found in platelets and leukemic and neuronal tissues; XPLN
• Gene Name: ARHGEF3
• UniProt ID: ARHG3_HUMAN
• Pfam ID: PF00621
• Sequence:
  MVAKDYPFYLTVKRANCSLELPPASGPAKDAEEPSNKRVKPLSRVTSLANLIPPVKATPL
  KRFSQTLQRSISFRSESRPDILAPRPWSRNAAPSSTKRRDSKLWSETFDVCVNQMLTSKE
  IKRQEAIFELSQGEEDLIEDLKLAKKAYHDPMLKLSIMTEQELNQIFGTLDSLIPLHEEL
  LSQLRDVRKPDGSTEHVGPILVGWLPCLSSYDSYCSNQVAAKALLDHKKQDHRVQDFLQR
  CLESPFSRKLDLWNFLDIPRSRLVKYPLLLREILRHTPNDNPDQQHLEEAINIIQGIVAE
  INTKTGESECRYYKERLLYLEEGQKDSLIDSSRVLCCHGELKNNRGVKLHVFLFQEVLVI
  TRAVTHNEQLCYQLYRQPIPVKDLLLEDLQDGEVRLGGSLRGAFSNNERIKNFFRVSFKN
  GSQSQTHSLQANDTFNKQQWLNCIRQAKETVLCAAGQAGVLDSEGSFLNPTTGSRELQGE
  TKLEQMDQSDSESDCSMDTSEVSLDCERMEQTDSSCGNSRHGESNV
• Function: Acts as a guanine nucleotide exchange factor (GEF) for RhoA and RhoB GTPases.
• Tissue Specificity: Widely expressed. Highest levels are found in adult brain and skeletal muscle. Lower levels are found in heart and kidney.
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

18 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 Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[11]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Rho guanine nucleotide exchange factor 3 (ARHGEF3).	[16]

References

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• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [11] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [12] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [13] 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.
• [14] 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.
• [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] 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.
• [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.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.