Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNJXCJ0)

• DOT Name: NF-kappa-B inhibitor-interacting Ras-like protein 2 (NKIRAS2)
• Synonyms: I-kappa-B-interacting Ras-like protein 2; Kappa B-Ras protein 2; KappaB-Ras2
• Gene Name: NKIRAS2
• Related Disease:
  Glioblastoma multiforme
  Nasopharyngeal carcinoma
• UniProt ID: KBRS2_HUMAN
• Pfam ID: PF00071
• Sequence:
  MGKSCKVVVCGQASVGKTSILEQLLYGNHVVGSEMIETQEDIYVGSIETDRGVREQVRFY
  DTRGLRDGAELPRHCFSCTDGYVLVYSTDSRESFQRVELLKKEIDKSKDKKEVTIVVLGN
  KCDLQEQRRVDPDVAQHWAKSEKVKLWEVSVADRRSLLEPFVYLASKMTQPQSKSAFPLS
  RKNKGSGSLDG
• Function: Atypical Ras-like protein that acts as a potent regulator of NF-kappa-B activity by preventing the degradation of NF-kappa-B inhibitor beta (NFKBIB) by most signals, explaining why NFKBIB is more resistant to degradation. May act by blocking phosphorylation of NFKBIB and nuclear localization of p65/RELA NF-kappa-B subunit. It is unclear whether it acts as a GTPase. Both GTP- and GDP-bound forms block phosphorylation of NFKBIB.
• Tissue Specificity: Widely expressed.
• Reactome Pathway:
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of NF-kappa-B inhibitor-interacting Ras-like protein 2 (NKIRAS2).	[3]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of NF-kappa-B inhibitor-interacting Ras-like protein 2 (NKIRAS2).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of NF-kappa-B inhibitor-interacting Ras-like protein 2 (NKIRAS2).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NF-kappa-B inhibitor-interacting Ras-like protein 2 (NKIRAS2).	[5]

References

• [1] miR-125b controls apoptosis and temozolomide resistance by targeting TNFAIP3 and NKIRAS2 in glioblastomas.Cell Death Dis. 2014 Jun 5;5(6):e1279. doi: 10.1038/cddis.2014.245.
• [2] Epstein-Barr virus-coded miR-BART13 promotes nasopharyngeal carcinoma cell growth and metastasis via targeting of the NKIRAS2/NF-B pathway.Cancer Lett. 2019 Apr 10;447:33-40. doi: 10.1016/j.canlet.2019.01.022. Epub 2019 Jan 23.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] 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.