Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0FSRW7)

• DOT Name: Regulator of G-protein signaling 2 (RGS2)
• Synonyms: RGS2; Cell growth-inhibiting gene 31 protein; G0/G1 switch regulatory protein 8
• Gene Name: RGS2
• UniProt ID: RGS2_HUMAN
• PDB ID: 2AF0; 2V4Z; 4EKC; 4EKD
• Pfam ID: PF00615
• Sequence:
  MQSAMFLAVQHDCRPMDKSAGSGHKSEEKREKMKRTLLKDWKTRLSYFLQNSSTPGKPKT
  GKKSKQQAFIKPSPEEAQLWSEAFDELLASKYGLAAFRAFLKSEFCEENIEFWLACEDFK
  KTKSPQKLSSKARKIYTDFIEKEAPKEINIDFQTKTLIAQNIQEATSGCFTTAQKRVYSL
  MENNSYPRFLESEFYQDLCKKPQITTEPHAT
• Function: Regulates G protein-coupled receptor signaling cascades. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. It is involved in the negative regulation of the angiotensin-activated signaling pathway. Plays a role in the regulation of blood pressure in response to signaling via G protein-coupled receptors and GNAQ. Plays a role in regulating the constriction and relaxation of vascular smooth muscle. Binds EIF2B5 and blocks its activity, thereby inhibiting the translation of mRNA into protein.
• Tissue Specificity: Expressed in acute myelogenous leukemia (AML) and in acute lymphoblastic leukemia (ALL).
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Olfactory transduction (hsa04740)
  Oxytocin sig.ling pathway (hsa04921)
• Reactome Pathway: G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Regulator of G-protein signaling 2 (RGS2) affects the response to substance of Mitoxantrone.	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Regulator of G-protein signaling 2 (RGS2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Regulator of G-protein signaling 2 (RGS2).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Regulator of G-protein signaling 2 (RGS2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Regulator of G-protein signaling 2 (RGS2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Regulator of G-protein signaling 2 (RGS2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Regulator of G-protein signaling 2 (RGS2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Regulator of G-protein signaling 2 (RGS2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Regulator of G-protein signaling 2 (RGS2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Regulator of G-protein signaling 2 (RGS2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Regulator of G-protein signaling 2 (RGS2).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Regulator of G-protein signaling 2 (RGS2).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Regulator of G-protein signaling 2 (RGS2).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[16]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Regulator of G-protein signaling 2 (RGS2).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[18]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[19]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Regulator of G-protein signaling 2 (RGS2).	[20]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Regulator of G-protein signaling 2 (RGS2).	[21]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Regulator of G-protein signaling 2 (RGS2).	[22]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[23]
Lindane	DMB8CNL	Approved	Lindane decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[24]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[25]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Regulator of G-protein signaling 2 (RGS2).	[26]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Regulator of G-protein signaling 2 (RGS2).	[25]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Regulator of G-protein signaling 2 (RGS2).	[27]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of Regulator of G-protein signaling 2 (RGS2).	[28]
Coprexa	DMA0WEK	Phase 3	Coprexa increases the expression of Regulator of G-protein signaling 2 (RGS2).	[29]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Regulator of G-protein signaling 2 (RGS2).	[30]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Regulator of G-protein signaling 2 (RGS2).	[31]
Lithium	DMZ3OU6	Phase 2	Lithium increases the expression of Regulator of G-protein signaling 2 (RGS2).	[33]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[35]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Regulator of G-protein signaling 2 (RGS2).	[36]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Regulator of G-protein signaling 2 (RGS2).	[37]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Regulator of G-protein signaling 2 (RGS2).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Regulator of G-protein signaling 2 (RGS2).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Regulator of G-protein signaling 2 (RGS2).	[40]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Regulator of G-protein signaling 2 (RGS2).	[41]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[42]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Regulator of G-protein signaling 2 (RGS2).	[43]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Regulator of G-protein signaling 2 (RGS2).	[24]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Regulator of G-protein signaling 2 (RGS2).	[44]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Regulator of G-protein signaling 2 (RGS2).	[45]
Manganese	DMKT129	Investigative	Manganese increases the expression of Regulator of G-protein signaling 2 (RGS2).	[46]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the degradation of Regulator of G-protein signaling 2 (RGS2).	[32]

References

• [1] 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.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Real-time monitoring of cisplatin-induced cell death. PLoS One. 2011;6(5):e19714. doi: 10.1371/journal.pone.0019714. Epub 2011 May 16.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Gene expression profile changes in NB4 cells induced by arsenic trioxide. Acta Pharmacol Sin. 2003 Jul;24(7):646-50.
• [12] 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.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [15] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [16] 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.
• [17] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [18] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [19] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [20] Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
• [21] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [22] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [23] Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 2017 Nov;32(11):2400-2413. doi: 10.1002/tox.22453. Epub 2017 Aug 10.
• [24] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [25] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [28] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [29] Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chem Biol Interact. 2023 Sep 1;382:110546. doi: 10.1016/j.cbi.2023.110546. Epub 2023 Jun 7.
• [30] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [31] Upregulation of genes orchestrating keratinocyte differentiation, including the novel marker gene ID2, by contact sensitizers in human bulge-derived keratinocytes. J Biochem Mol Toxicol. 2010 Jan-Feb;24(1):10-20.
• [32] Cholesterol increases protein levels of the E3 ligase MARCH6 and thereby stimulates protein degradation. J Biol Chem. 2019 Feb 15;294(7):2436-2448. doi: 10.1074/jbc.RA118.005069. Epub 2018 Dec 13.
• [33] A genetic network model of cellular responses to lithium treatment and cocaine abuse in bipolar disorder. BMC Syst Biol. 2010 Nov 19;4:158. doi: 10.1186/1752-0509-4-158.
• [34] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [35] 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.
• [36] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [37] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [38] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [39] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [40] 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.
• [41] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [42] 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.
• [43] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [44] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [45] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [46] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [47] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.