Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWQN0DP)

• DOT Name: GTPase HRas (HRAS)
• Synonyms: EC 3.6.5.2; H-Ras-1; Ha-Ras; Transforming protein p21; c-H-ras; p21ras
• Gene Name: HRAS
• Related Disease:
  Costello syndrome
  Rhabdomyosarcoma
  Noonan syndrome-like disorder with loose anagen hair
• UniProt ID: RASH_HUMAN
• PDB ID: 121P ; 1AA9 ; 1AGP ; 1BKD ; 1CLU ; 1CRP ; 1CRQ ; 1CRR ; 1CTQ ; 1GNP ; 1GNQ ; 1GNR ; 1HE8 ; 1IAQ ; 1IOZ ; 1JAH ; 1JAI ; 1K8R ; 1LF0 ; 1LF5 ; 1LFD ; 1NVU ; 1NVV ; 1NVW ; 1NVX ; 1P2S ; 1P2T ; 1P2U ; 1P2V ; 1PLJ ; 1PLK ; 1PLL ; 1Q21 ; 1QRA ; 1RVD ; 1WQ1 ; 1XCM ; 1XD2 ; 1XJ0 ; 1ZVQ ; 1ZW6 ; 221P ; 2C5L ; 2CE2 ; 2CL0 ; 2CL6 ; 2CL7 ; 2CLC ; 2CLD ; 2EVW ; 2LCF ; 2LWI ; 2N42 ; 2N46 ; 2Q21 ; 2QUZ ; 2RGA ; 2RGB ; 2RGC ; 2RGD ; 2RGE ; 2RGG ; 2UZI ; 2VH5 ; 2X1V ; 3DDC ; 3I3S ; 3K8Y ; 3K9L ; 3K9N ; 3KKM ; 3KKN ; 3KUD ; 3L8Y ; 3L8Z ; 3LBH ; 3LBI ; 3LBN ; 3LO5 ; 3OIU ; 3OIV ; 3OIW ; 3RRY ; 3RRZ ; 3RS0 ; 3RS2 ; 3RS3 ; 3RS4 ; 3RS5 ; 3RS7 ; 3RSL ; 3RSO ; 3TGP ; 421P ; 4DLR ; 4DLS ; 4DLT ; 4DLU ; 4DLV ; 4DLW ; 4DLX ; 4DLY ; 4DLZ ; 4DST ; 4DSU ; 4EFL ; 4EFM ; 4EFN ; 4G0N ; 4G3X ; 4K81 ; 4L9S ; 4L9W ; 4NYI ; 4NYJ ; 4NYM ; 4Q21 ; 4RSG ; 4URU ; 4URV ; 4URW ; 4URX ; 4URY ; 4URZ ; 4US0 ; 4US1 ; 4US2 ; 4XVQ ; 4XVR ; 521P ; 5B2Z ; 5B30 ; 5E95 ; 5P21 ; 5VBE ; 5VBZ ; 5WDO ; 5WDP ; 5WDQ ; 5WFO ; 5WFP ; 5WFQ ; 5WFR ; 5WPL ; 5X9S ; 5ZC6 ; 621P ; 6AMB ; 6AXG ; 6BVI ; 6BVJ ; 6BVK ; 6BVL ; 6BVM ; 6CUO ; 6CUP ; 6CUR ; 6D55 ; 6D56 ; 6D59 ; 6D5E ; 6D5G ; 6D5H ; 6D5J ; 6D5L ; 6D5M ; 6D5V ; 6D5W ; 6DZH ; 6E6C ; 6E6P ; 6MQT ; 6NTC ; 6NTD ; 6Q21 ; 6V94 ; 6V9F ; 6V9J ; 6V9L ; 6V9M ; 6V9N ; 6V9O ; 6ZJ0 ; 6ZL3 ; 721P ; 7DPH ; 7DPJ ; 7JHP ; 7JIF ; 7JIG ; 7JIH ; 7JII ; 7L0F ; 7L0G ; 7OG9 ; 7OGA ; 7OGB ; 7OGC ; 7OGD ; 7OGE ; 7OGF ; 7TAM ; 7VV8 ; 7VV9 ; 7VVG ; 821P ; 8BE6 ; 8BE7 ; 8BE8 ; 8BE9 ; 8BEA ; 8BOS ; 8BWG ; 8CNJ ; 8CNN ; 8ELK ; 8ELR ; 8ELS ; 8ELT ; 8ELU ; 8ELV ; 8ELW ; 8ELX ; 8ELY ; 8ELZ ; 8EM0 ; 8FG3 ; 8FG4
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG
  QEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHQYREQIKRVKDSDDVPMVLVGNKCDL
  AARTVESRQAQDLARSYGIPYIETSAKTRQGVEDAFYTLVREIRQHKLRKLNPPDESGPG
  CMSCKCVLS
• Function: Involved in the activation of Ras protein signal transduction. Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
• Tissue Specificity: Widely expressed.
• 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)
  Endocytosis (hsa04144)
  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)
  Focal adhesion (hsa04510)
  Gap junction (hsa04540)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  C-type lectin receptor sig.ling pathway (hsa04625)
  JAK-STAT sig.ling pathway (hsa04630)
  .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)
  Salmonella infection (hsa05132)
  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)
  EPHB-mediated forward signaling (R-HSA-3928662)
  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)
  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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Costello syndrome	DISXVJH3	Definitive	Autosomal dominant	[1]
Rhabdomyosarcoma	DISNR7MS	Moderate	Autosomal dominant	[2]
Noonan syndrome-like disorder with loose anagen hair	DISWMZIV	Disputed	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	GTPase HRas (HRAS) decreases the response to substance of Cisplatin.	[37]
Capecitabine	DMTS85L	Approved	GTPase HRas (HRAS) decreases the response to substance of Capecitabine.	[38]
Piperazinyl methyl quinazolinone derivative 2	DM913KS	Patented	GTPase HRas (HRAS) increases the response to substance of Piperazinyl methyl quinazolinone derivative 2.	[39]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mononitrophenol	DM4QO9G	Investigative	GTPase HRas (HRAS) affects the glucuronidation of Mononitrophenol.	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of GTPase HRas (HRAS).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of GTPase HRas (HRAS).	[8]
Lovastatin	DM9OZWQ	Approved	Lovastatin decreases the prenylation of GTPase HRas (HRAS).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of GTPase HRas (HRAS).	[28]
ABT-100	DMPFLS5	Terminated	ABT-100 decreases the farnesylation of GTPase HRas (HRAS).	[30]

30 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 GTPase HRas (HRAS).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of GTPase HRas (HRAS).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GTPase HRas (HRAS).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of GTPase HRas (HRAS).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of GTPase HRas (HRAS).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of GTPase HRas (HRAS).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of GTPase HRas (HRAS).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of GTPase HRas (HRAS).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of GTPase HRas (HRAS).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of GTPase HRas (HRAS).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of GTPase HRas (HRAS).	[16]
Hydroquinone	DM6AVR4	Approved	Hydroquinone affects the expression of GTPase HRas (HRAS).	[17]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of GTPase HRas (HRAS).	[12]
Malathion	DMXZ84M	Approved	Malathion increases the expression of GTPase HRas (HRAS).	[18]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of GTPase HRas (HRAS).	[19]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of GTPase HRas (HRAS).	[20]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid increases the activity of GTPase HRas (HRAS).	[22]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the expression of GTPase HRas (HRAS).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the mutagenesis of GTPase HRas (HRAS).	[24]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the expression of GTPase HRas (HRAS).	[25]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of GTPase HRas (HRAS).	[15]
Salirasib	DMRSU4X	Phase 2	Salirasib decreases the expression of GTPase HRas (HRAS).	[27]
MANUMYCIN A	DM1SWOY	Terminated	MANUMYCIN A decreases the expression of GTPase HRas (HRAS).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of GTPase HRas (HRAS).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of GTPase HRas (HRAS).	[32]
Paraquat	DMR8O3X	Investigative	Paraquat affects the splicing of GTPase HRas (HRAS).	[33]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the mutagenesis of GTPase HRas (HRAS).	[34]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the activity of GTPase HRas (HRAS).	[35]
Naringin	DM4DG1Y	Investigative	Naringin increases the activity of GTPase HRas (HRAS).	[36]
18beta-Glycyrrhetic acid	DMFMRN8	Investigative	18beta-Glycyrrhetic acid decreases the expression of GTPase HRas (HRAS).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the localization of GTPase HRas (HRAS).	[14]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Zarnestra	DMF30HL	Phase 3	Zarnestra decreases the metabolism of GTPase HRas (HRAS).	[26]

References

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