Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOQ4AZ9)

• DOT Name: NFATC2-interacting protein (NFATC2IP)
• Synonyms: 45 kDa NF-AT-interacting protein; 45 kDa NFAT-interacting protein; Nuclear factor of activated T-cells, cytoplasmic 2-interacting protein
• Gene Name: NFATC2IP
• UniProt ID: NF2IP_HUMAN
• PDB ID: 2JXX; 2L76; 3RD2
• Pfam ID: PF11976
• Sequence:
  MAEPVGKRGRWSGGSGAGRGGRGGWGGRGRRPRAQRSPSRGTLDVVSVDLVTDSDEEILE
  VATARGAADEVEVEPPEPPGPVASRDNSNSDSEGEDRRPAGPPREPVRRRRRLVLDPGEA
  PLVPVYSGKVKSSLRLIPDDLSLLKLYPPGDEEEAELADSSGLYHEGSPSPGSPWKTKLR
  TKDKEEKKKTEFLDLDNSPLSPPSPRTKSRTHTRALKKLSEVNKRLQDLRSCLSPKPPQG
  QEQQGQEDEVVLVEGPTLPETPRLFPLKIRCRADLVRLPLRMSEPLQSVVDHMATHLGVS
  PSRILLLFGETELSPTATPRTLKLGVADIIDCVVLTSSPEATETSQQLQLRVQGKEKHQT
  LEVSLSRDSPLKTLMSHYEEAMGLSGRKLSFFFDGTKLSGRELPADLGMESGDLIEVWG
• Function: In T-helper 2 (Th2) cells, regulates the magnitude of NFAT-driven transcription of a specific subset of cytokine genes, including IL3, IL4, IL5 and IL13, but not IL2. Recruits PRMT1 to the IL4 promoter; this leads to enhancement of histone H4 'Arg-3'-methylation and facilitates subsequent histone acetylation at the IL4 locus, thus promotes robust cytokine expression. Down-regulates formation of poly-SUMO chains by UBE2I/UBC9.

Molecular Interaction Atlas (MIA) of This DOT

11 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 NFATC2-interacting protein (NFATC2IP).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NFATC2-interacting protein (NFATC2IP).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of NFATC2-interacting protein (NFATC2IP).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NFATC2-interacting protein (NFATC2IP).	[4]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of NFATC2-interacting protein (NFATC2IP).	[6]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of NFATC2-interacting protein (NFATC2IP).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of NFATC2-interacting protein (NFATC2IP).	[8]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of NFATC2-interacting protein (NFATC2IP).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of NFATC2-interacting protein (NFATC2IP).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of NFATC2-interacting protein (NFATC2IP).	[3]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of NFATC2-interacting protein (NFATC2IP).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of NFATC2-interacting protein (NFATC2IP).	[5]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of NFATC2-interacting protein (NFATC2IP).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of NFATC2-interacting protein (NFATC2IP).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NFATC2-interacting protein (NFATC2IP).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of NFATC2-interacting protein (NFATC2IP).	[5]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [4] 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.
• [5] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [6] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [7] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [10] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.