Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9UKTQ5)

• DOT Name: Rho guanine nucleotide exchange factor 39 (ARHGEF39)
• Gene Name: ARHGEF39
• Related Disease:
  Advanced cancer
  Neoplasm
  Non-small-cell lung cancer
  Gastric cancer
  Hepatocellular carcinoma
  Specific language impairment
  Stomach cancer
• UniProt ID: ARG39_HUMAN
• Pfam ID: PF00169 ; PF00621
• Sequence:
  MELSCPGSRCPVQEQRARWERKRACTARELLETERRYQEQLGLVATYFLGILKAKGTLRP
  PERQALFGSWELIYGASQELLPYLEGGCWGQGLEGFCRHLELYNQFAANSERSQTTLQEQ
  LKKNKGFRRFVRLQEGRPEFGGLQLQDLLPLPLQRLQQYENLVVALAENTGPNSPDHQQL
  TRAARLISETAQRVHTIGQKQKNDQHLRRVQALLSGRQAKGLTSGRWFLRQGWLLVVPPH
  GEPRPRMFFLFTDVLLMAKPRPPLHLLRSGTFACKALYPMAQCHLSRVFGHSGGPCGGLL
  SLSFPHEKLLLMSTDQEELSRWYHSLTWAISSQKN
• Function: Promotes cell proliferation.
• Tissue Specificity: Strongly expressed in hepatocellular carcinoma (HCC) compared with their non-cancerous counterparts.
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  RAC1 GTPase cycle (R-HSA-9013149)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Limited	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[1]
Specific language impairment	DISEKRML	Limited	Genetic Variation	[4]
Stomach cancer	DISKIJSX	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[10]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Rho guanine nucleotide exchange factor 39 (ARHGEF39).	[19]

References

• [1] Expression of Rho Guanine Nucleotide Exchange Factor 39 (ARHGEF39) and Its Prognostic Significance in Hepatocellular Carcinoma.Med Sci Monit. 2019 Oct 18;25:7826-7835. doi: 10.12659/MSM.918270.
• [2] ARHGEF39 promotes tumor progression via activation of Rac1/P38 MAPK/ATF2 signaling and predicts poor prognosis in non-small cell lung cancer patients.Lab Invest. 2018 May;98(5):670-681. doi: 10.1038/s41374-018-0022-y. Epub 2018 Jan 30.
• [3] ARHGEF39 promotes gastric cancer cell proliferation and migration via Akt signaling pathway.Mol Cell Biochem. 2018 Mar;440(1-2):33-42. doi: 10.1007/s11010-017-3153-3. Epub 2017 Sep 4.
• [4] Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders.Mol Psychiatry. 2018 May;23(5):1375-1384. doi: 10.1038/mp.2017.30. Epub 2017 Mar 14.
• [5] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [12] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [13] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [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] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.