Details of Drug Off-Target (DOT)

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

• DOT Name: NF-kappa-B inhibitor-interacting Ras-like protein 1 (NKIRAS1)
• Synonyms: I-kappa-B-interacting Ras-like protein 1; Kappa B-Ras protein 1; KappaB-Ras1
• Gene Name: NKIRAS1
• UniProt ID: KBRS1_HUMAN
• Pfam ID: PF00071
• Sequence:
  MGKGCKVVVCGLLSVGKTAILEQLLYGNHTIGMEDCETMEDVYMASVETDRGVKEQLHLY
  DTRGLQEGVELPKHYFSFADGFVLVYSVNNLESFQRVELLKKEIDKFKDKKEVAIVVLGN
  KIDLSEQRQVDAEVAQQWAKSEKVRLWEVTVTDRKTLIEPFTLLASKLSQPQSKSSFPLP
  GRKNKGNSNSEN
• 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 mediating cytoplasmic retention 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

9 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 1 (NKIRAS1).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NF-kappa-B inhibitor-interacting Ras-like protein 1 (NKIRAS1).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of NF-kappa-B inhibitor-interacting Ras-like protein 1 (NKIRAS1).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of NF-kappa-B inhibitor-interacting Ras-like protein 1 (NKIRAS1).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of NF-kappa-B inhibitor-interacting Ras-like protein 1 (NKIRAS1).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of NF-kappa-B inhibitor-interacting Ras-like protein 1 (NKIRAS1).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of NF-kappa-B inhibitor-interacting Ras-like protein 1 (NKIRAS1).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of NF-kappa-B inhibitor-interacting Ras-like protein 1 (NKIRAS1).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of NF-kappa-B inhibitor-interacting Ras-like protein 1 (NKIRAS1).	[9]

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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [6] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [7] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.