Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVQ1DG3)

DOT Name	GTPase NRas (NRAS)
Synonyms	EC 3.6.5.2; Transforming protein N-Ras
Gene Name	NRAS
Related Disease	Noonan syndrome ( ) Noonan syndrome 6 ( ) Cardiofaciocutaneous syndrome ( ) Costello syndrome ( ) Noonan syndrome with multiple lentigines ( )
UniProt ID	RASN_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2N9C; 3CON; 5UHV; 6E6H; 6MPP; 6ULI; 6ULK; 6ULN; 6ULR; 6UON; 6WGH; 6ZIO; 6ZIR; 6ZIZ; 7F68; 7OW3; 7OW4; 7OW5; 7OW6; 7PB2
EC Number	3.6.5.2
Pfam ID	PF00071
Sequence	MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG QEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVLVGNKCDL PTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMKKLNSSDDGTQG CMGLPCVVM
Function	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
KEGG Pathway	EGFR tyrosine ki.se inhibitor resistance (hsa01521 ) Endocrine resistance (hsa01522 ) MAPK sig.ling pathway (hsa04010 ) ErbB sig.ling pathway (hsa04012 ) Ras sig.ling pathway (hsa04014 ) Rap1 sig.ling pathway (hsa04015 ) Chemokine sig.ling pathway (hsa04062 ) FoxO sig.ling pathway (hsa04068 ) Sphingolipid sig.ling pathway (hsa04071 ) Phospholipase D sig.ling pathway (hsa04072 ) Mitophagy - animal (hsa04137 ) Autophagy - animal (hsa04140 ) mTOR sig.ling pathway (hsa04150 ) PI3K-Akt sig.ling pathway (hsa04151 ) Apoptosis (hsa04210 ) Longevity regulating pathway (hsa04211 ) Longevity regulating pathway - multiple species (hsa04213 ) Cellular senescence (hsa04218 ) Axon guidance (hsa04360 ) VEGF sig.ling pathway (hsa04370 ) Apelin sig.ling pathway (hsa04371 ) Gap junction (hsa04540 ) Sig.ling pathways regulating pluripotency of stem cells (hsa04550 ) C-type lectin receptor sig.ling pathway (hsa04625 ) .tural killer cell mediated cytotoxicity (hsa04650 ) T cell receptor sig.ling pathway (hsa04660 ) B cell receptor sig.ling pathway (hsa04662 ) Fc epsilon RI sig.ling pathway (hsa04664 ) Thermogenesis (hsa04714 ) Long-term potentiation (hsa04720 ) Neurotrophin sig.ling pathway (hsa04722 ) Cholinergic sy.pse (hsa04725 ) Serotonergic sy.pse (hsa04726 ) Long-term depression (hsa04730 ) Regulation of actin cytoskeleton (hsa04810 ) Insulin sig.ling pathway (hsa04910 ) GnRH sig.ling pathway (hsa04912 ) Estrogen sig.ling pathway (hsa04915 ) Melanogenesis (hsa04916 ) Prolactin sig.ling pathway (hsa04917 ) Thyroid hormone sig.ling pathway (hsa04919 ) Oxytocin sig.ling pathway (hsa04921 ) Relaxin sig.ling pathway (hsa04926 ) GnRH secretion (hsa04929 ) AGE-RAGE sig.ling pathway in diabetic complications (hsa04933 ) Growth hormone synthesis, secretion and action (hsa04935 ) Alzheimer disease (hsa05010 ) Pathways of neurodegeneration - multiple diseases (hsa05022 ) Alcoholism (hsa05034 ) Hepatitis C (hsa05160 ) Hepatitis B (hsa05161 ) Human cytomegalovirus infection (hsa05163 ) Human papillomavirus infection (hsa05165 ) Human T-cell leukemia virus 1 infection (hsa05166 ) Kaposi sarcoma-associated herpesvirus infection (hsa05167 ) Human immunodeficiency virus 1 infection (hsa05170 ) Pathways in cancer (hsa05200 ) Viral carcinogenesis (hsa05203 ) Proteoglycans in cancer (hsa05205 ) MicroR.s in cancer (hsa05206 ) Chemical carcinogenesis - receptor activation (hsa05207 ) Chemical carcinogenesis - reactive oxygen species (hsa05208 ) Colorectal cancer (hsa05210 ) Re.l cell carcinoma (hsa05211 ) Endometrial cancer (hsa05213 ) Glioma (hsa05214 ) Prostate cancer (hsa05215 ) Thyroid cancer (hsa05216 ) Melanoma (hsa05218 ) Bladder cancer (hsa05219 ) Chronic myeloid leukemia (hsa05220 ) Acute myeloid leukemia (hsa05221 ) Non-small cell lung cancer (hsa05223 ) Breast cancer (hsa05224 ) Hepatocellular carcinoma (hsa05225 ) Gastric cancer (hsa05226 ) Central carbon metabolism in cancer (hsa05230 ) Choline metabolism in cancer (hsa05231 ) PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235 ) Lipid and atherosclerosis (hsa05417 )
Reactome Pathway	Activation of RAS in B cells (R-HSA-1169092 ) Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants (R-HSA-1236382 ) SHC1 events in ERBB2 signaling (R-HSA-1250196 ) SHC1 events in ERBB4 signaling (R-HSA-1250347 ) Signaling by SCF-KIT (R-HSA-1433557 ) Signalling to RAS (R-HSA-167044 ) p38MAPK events (R-HSA-171007 ) GRB2 events in EGFR signaling (R-HSA-179812 ) SHC1 events in EGFR signaling (R-HSA-180336 ) Downstream signal transduction (R-HSA-186763 ) GRB2 events in ERBB2 signaling (R-HSA-1963640 ) Tie2 Signaling (R-HSA-210993 ) EGFR Transactivation by Gastrin (R-HSA-2179392 ) DAP12 signaling (R-HSA-2424491 ) SHC-related events triggered by IGF1R (R-HSA-2428933 ) FCERI mediated MAPK activation (R-HSA-2871796 ) NCAM signaling for neurite out-growth (R-HSA-375165 ) Ras activation upon Ca2+ influx through NMDA receptor (R-HSA-442982 ) VEGFR2 mediated cell proliferation (R-HSA-5218921 ) CD209 (DC-SIGN) signaling (R-HSA-5621575 ) Constitutive Signaling by EGFRvIII (R-HSA-5637810 ) SHC-mediated cascade (R-HSA-5654688 ) FRS-mediated FGFR1 signaling (R-HSA-5654693 ) SHC-mediated cascade (R-HSA-5654699 ) FRS-mediated FGFR2 signaling (R-HSA-5654700 ) SHC-mediated cascade (R-HSA-5654704 ) FRS-mediated FGFR3 signaling (R-HSA-5654706 ) FRS-mediated FGFR4 signaling (R-HSA-5654712 ) SHC-mediated cascade (R-HSA-5654719 ) Signaling by FGFR2 in disease (R-HSA-5655253 ) Signaling by FGFR4 in disease (R-HSA-5655291 ) Signaling by FGFR1 in disease (R-HSA-5655302 ) Signaling by FGFR3 in disease (R-HSA-5655332 ) Regulation of RAS by GAPs (R-HSA-5658442 ) RAF activation (R-HSA-5673000 ) RAF/MAP kinase cascade (R-HSA-5673001 ) MAP2K and MAPK activation (R-HSA-5674135 ) Negative regulation of MAPK pathway (R-HSA-5675221 ) Neutrophil degranulation (R-HSA-6798695 ) Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946 ) Signaling by high-kinase activity BRAF mutants (R-HSA-6802948 ) Signaling by BRAF and RAF1 fusions (R-HSA-6802952 ) RAS signaling downstream of NF1 loss-of-function variants (R-HSA-6802953 ) Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955 ) Insulin receptor signalling cascade (R-HSA-74751 ) PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases (R-HSA-8849471 ) MET activates RAS signaling (R-HSA-8851805 ) Activated NTRK2 signals through RAS (R-HSA-9026519 ) Erythropoietin activates RAS (R-HSA-9027284 ) Activated NTRK2 signals through FRS2 and FRS3 (R-HSA-9028731 ) Activated NTRK3 signals through RAS (R-HSA-9034864 ) FLT3 Signaling (R-HSA-9607240 ) Constitutive Signaling by Overexpressed ERBB2 (R-HSA-9634285 ) Estrogen-stimulated signaling through PRKCZ (R-HSA-9634635 ) RAS processing (R-HSA-9648002 ) Signaling downstream of RAS mutants (R-HSA-9649948 ) Signaling by RAF1 mutants (R-HSA-9656223 ) Signaling by ERBB2 KD Mutants (R-HSA-9664565 ) Signaling by ERBB2 ECD mutants (R-HSA-9665348 ) Signaling by ERBB2 TMD/JMD mutants (R-HSA-9665686 ) Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants (R-HSA-9670439 ) Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants (R-HSA-9673767 ) Signaling by PDGFRA extracellular domain mutants (R-HSA-9673770 ) Signaling by FLT3 fusion proteins (R-HSA-9703465 ) Signaling by FLT3 ITD and TKD mutants (R-HSA-9703648 ) Signaling by RAS GAP mutants (R-HSA-9753510 ) Signaling by RAS GTPase mutants (R-HSA-9753512 ) SOS-mediated signalling (R-HSA-112412 )

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Noonan syndrome	DIS7Q7DN	Definitive	Autosomal dominant	[1]
Noonan syndrome 6	DISV60W2	Definitive	Autosomal dominant	[2]
Cardiofaciocutaneous syndrome	DISZJKSC	Strong	Autosomal dominant	[2]
Costello syndrome	DISXVJH3	Limited	Autosomal dominant	[1]
Noonan syndrome with multiple lentigines	DIS014D0	Limited	Autosomal dominant	[1]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	GTPase NRas (NRAS) increases the response to substance of Methotrexate.	[22]
Vemurafenib	DM62UG5	Approved	GTPase NRas (NRAS) affects the response to substance of Vemurafenib.	[23]
Pemetrexed	DMMX2E6	Approved	GTPase NRas (NRAS) increases the response to substance of Pemetrexed.	[22]
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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 GTPase NRas (NRAS).	[3]
Lovastatin	DM9OZWQ	Approved	Lovastatin decreases the prenylation of GTPase NRas (NRAS).	[17]
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18 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of GTPase NRas (NRAS).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GTPase NRas (NRAS).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of GTPase NRas (NRAS).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of GTPase NRas (NRAS).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GTPase NRas (NRAS).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of GTPase NRas (NRAS).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of GTPase NRas (NRAS).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of GTPase NRas (NRAS).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of GTPase NRas (NRAS).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of GTPase NRas (NRAS).	[13]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of GTPase NRas (NRAS).	[12]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of GTPase NRas (NRAS).	[14]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of GTPase NRas (NRAS).	[15]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the expression of GTPase NRas (NRAS).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of GTPase NRas (NRAS).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of GTPase NRas (NRAS).	[19]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of GTPase NRas (NRAS).	[20]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the expression of GTPase NRas (NRAS).	[21]
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⏷ Show the Full List of 18 Drug(s)

References

1	Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
2	A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2010 Jan;42(1):27-9. doi: 10.1038/ng.497. Epub 2009 Dec 6.
3	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.
4	Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
5	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.
6	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
7	Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells. J Signal Transduct. 2012;2012:204236. doi: 10.1155/2012/204236. Epub 2012 Oct 9.
8	Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
9	Genome-wide analysis of BEAS-2B cells exposed to trivalent arsenicals and dimethylthioarsinic acid. Toxicology. 2010 Jan 31;268(1-2):31-9.
10	Quercetin inhibits p21-RAS expression in human colon cancer cell lines and in primary colorectal tumors. Int J Cancer. 2000 Feb 1;85(3):438-45.
11	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.
12	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.
13	Poly(ADP-ribosyl)ation enhances H-RAS protein stability and causes abnormal cell cycle progression in human TK6 lymphoblastoid cells treated with hydroquinone. Chem Biol Interact. 2015 Aug 5;238:1-8. doi: 10.1016/j.cbi.2015.05.019. Epub 2015 Jun 3.
14	Daunorubicin-induced variations in gene transcription: commitment to proliferation arrest, senescence and apoptosis. Biochem J. 2003 Jun 15;372(Pt 3):703-11. doi: 10.1042/BJ20021950.
15	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.
16	Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
17	Combining prenylation inhibitors causes synergistic cytotoxicity, apoptosis and disruption of RAS-to-MAP kinase signalling in multiple myeloma cells. Br J Haematol. 2005 Sep;130(6):912-25. doi: 10.1111/j.1365-2141.2005.05696.x.
18	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.
19	Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
20	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.
21	Alterations in transcription and protein expressions of HCC-related genes in HepG2 cells caused by microcystin-LR. Toxicol In Vitro. 2017 Apr;40:115-123. doi: 10.1016/j.tiv.2016.12.016. Epub 2017 Jan 3.
22	KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol Cancer Ther. 2014 Jun;13(6):1611-24. doi: 10.1158/1535-7163.MCT-13-0649. Epub 2014 Mar 31.
23	Paradoxical activation of MEK/ERK signaling induced by B-Raf inhibition enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Sci Rep. 2016 May 25;6:26803. doi: 10.1038/srep26803.