Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTW2R9X)

• DTT Name: GTPase NRas (NRAS)
• Synonyms: Transforming protein N-Ras; HRAS1
• Gene Name: NRAS
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Small GTPase
• UniProt ID: RASN_HUMAN
• TTD ID: T35486
• Sequence:
  MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG
  QEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVLVGNKCDL
  PTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMKKLNSSDDGTQG
  CMGLPCVVM
• Function: Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
• KEGG Pathway:
  EGFR tyrosine kinase inhibitor resistance (hsa01521)
  Endocrine resistance (hsa01522)
  MAPK signaling pathway (hsa04010)
  ErbB signaling pathway (hsa04012)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  Chemokine signaling pathway (hsa04062)
  FoxO signaling pathway (hsa04068)
  Sphingolipid signaling pathway (hsa04071)
  Phospholipase D signaling pathway (hsa04072)
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  mTOR signaling pathway (hsa04150)
  PI3K-Akt signaling pathway (hsa04151)
  Apoptosis (hsa04210)
  Longevity regulating pathway (hsa04211)
  Longevity regulating pathway - multiple species (hsa04213)
  Cellular senescence (hsa04218)
  Axon guidance (hsa04360)
  VEGF signaling pathway (hsa04370)
  Apelin signaling pathway (hsa04371)
  Gap junction (hsa04540)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  C-type lectin receptor signaling pathway (hsa04625)
  Natural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor signaling pathway (hsa04660)
  B cell receptor signaling pathway (hsa04662)
  Fc epsilon RI signaling pathway (hsa04664)
  Thermogenesis (hsa04714)
  Long-term potentiation (hsa04720)
  Neurotrophin signaling pathway (hsa04722)
  Cholinergic synapse (hsa04725)
  Serotonergic synapse (hsa04726)
  Long-term depression (hsa04730)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin signaling pathway (hsa04910)
  GnRH signaling pathway (hsa04912)
  Estrogen signaling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Prolactin signaling pathway (hsa04917)
  Thyroid hormone signaling pathway (hsa04919)
  Oxytocin signaling pathway (hsa04921)
  Relaxin signaling pathway (hsa04926)
  GnRH secretion (hsa04929)
  AGE-RAGE signaling 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)
  MicroRNAs in cancer (hsa05206)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Colorectal cancer (hsa05210)
  Renal 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)
  p38MAPK events (R-HSA-171007)
  GRB2 events in EGFR signaling (R-HSA-179812)
  SHC1 events in EGFR signaling (R-HSA-180336)
  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)
  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)
  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)
  Insulin receptor signalling cascade (R-HSA-74751)
  SOS-mediated signalling (R-HSA-112412)

Molecular Interaction Atlas (MIA) of This DTT

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GI-4000	DMTY4PG	Colorectal cancer	2B91.Z	Phase 2	[2]
Mutant ras vaccine	DMM6KZR	Solid tumour/cancer	2A00-2F9Z	Phase 2	[1]
Reovirus	DMQ73AY	Head and neck cancer	2D42	Phase 2	[3]
Salirasib	DMRSU4X	Lung cancer	2C25.0	Phase 2	[4]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Perillyl alcohol	DMFWC3O	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[5]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
APC-300	DMNIEHV	Prostate cancer	2C82.0	Investigative	[5]
KA-10X	DM4GSHY	Solid tumour/cancer	2A00-2F9Z	Investigative	[5]

References

• [1] The immunological and clinical effects of mutated ras peptide vaccine in combination with IL-2, GM-CSF, or both in patients with solid tumors. J Transl Med. 2014 Feb 24;12:55.
• [2] Phase II study of the GI-4000 KRAS vaccine after curative therapy in patients with stage I-III lung adenocarcinoma harboring a KRAS G12C, G12D, or G12V mutation. Clin Lung Cancer. 2014 Nov;15(6):405-10.
• [3] Reovirus (Reolysin) as a potential therapy for malignant peripheral nerve sheath tumors.
• [4] The Ras inhibitor farnesylthiosalicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras: a potential treatment for cancer. Methods Enzymol. 2008;439:467-89.
• [5] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2823).