Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2TKG9P)

• DOT Name: 14-3-3 protein zeta/delta
• Synonyms: Protein kinase C inhibitor protein 1; KCIP-1
• Gene Name: YWHAZ
• Related Disease: Complex neurodevelopmental disorder
• UniProt ID: 1433Z_HUMAN
• PDB ID: 1IB1 ; 1QJA ; 1QJB ; 2C1J ; 2C1N ; 2O02 ; 2WH0 ; 3CU8 ; 3NKX ; 3RDH ; 4BG6 ; 4FJ3 ; 4HKC ; 4IHL ; 4N7G ; 4N7Y ; 4N84 ; 4WRQ ; 4ZDR ; 5D2D ; 5D3F ; 5EWZ ; 5EXA ; 5J31 ; 5JM4 ; 5M35 ; 5M36 ; 5M37 ; 5NAS ; 5ULO ; 5WXN ; 5XY9 ; 6EF5 ; 6EJL ; 6EWW ; 6F08 ; 6F09 ; 6FN9 ; 6FNA ; 6FNB ; 6FNC ; 6Q0K ; 6RLZ ; 6U2H ; 6XAG ; 6YMO ; 6YO8 ; 6YOS ; 6ZFD ; 6ZFG ; 7D8H ; 7D8P ; 7D9V ; 7MFD ; 7MFE ; 7MFF ; 7Q16 ; 7ZIT ; 8A9G ; 8AH2
• Pfam ID: PF00244
• Sequence:
  MDKNELVQKAKLAEQAERYDDMAACMKSVTEQGAELSNEERNLLSVAYKNVVGARRSSWR
  VVSSIEQKTEGAEKKQQMAREYREKIETELRDICNDVLSLLEKFLIPNASQAESKVFYLK
  MKGDYYRYLAEVAAGDDKKGIVDQSQQAYQEAFEISKKEMQPTHPIRLGLALNFSVFYYE
  ILNSPEKACSLAKTAFDEAIAELDTLSEESYKDSTLIMQLLRDNLTLWTSDTQGDEAEAG
  EGGEN
• Function: Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Promotes cytosolic retention and inactivation of TFEB transcription factor by binding to phosphorylated TFEB. Induces ARHGEF7 activity on RAC1 as well as lamellipodia and membrane ruffle formation. In neurons, regulates spine maturation through the modulation of ARHGEF7 activity.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  PI3K-Akt sig.ling pathway (hsa04151)
  Hippo sig.ling pathway (hsa04390)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  Rap1 signalling (R-HSA-392517)
  GP1b-IX-V activation signalling (R-HSA-430116)
  KSRP (KHSRP) binds and destabilizes mRNA (R-HSA-450604)
  Interleukin-3, Interleukin-5 and GM-CSF signaling (R-HSA-512988)
  RHO GTPases activate PKNs (R-HSA-5625740)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Chk1/Chk2(Cds1) mediated inactivation of Cyclin B (R-HSA-75035)
  NOTCH4 Activation and Transmission of Signal to the Nucleus (R-HSA-9013700)
  Negative regulation of NOTCH4 signaling (R-HSA-9604323)
  Regulation of localization of FOXO transcription factors (R-HSA-9614399)
  SARS-CoV-1 targets host intracellular signalling and regulatory pathways (R-HSA-9735871)
  SARS-CoV-2 targets host intracellular signalling and regulatory pathways (R-HSA-9755779)
  Activation of BAD and translocation to mitochondria (R-HSA-111447)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Moderate	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
PEITC	DMOMN31	Phase 2	14-3-3 protein zeta/delta affects the binding of PEITC.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of 14-3-3 protein zeta/delta.	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 14-3-3 protein zeta/delta.	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 14-3-3 protein zeta/delta.	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 14-3-3 protein zeta/delta.	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 14-3-3 protein zeta/delta.	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 14-3-3 protein zeta/delta.	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of 14-3-3 protein zeta/delta.	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of 14-3-3 protein zeta/delta.	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of 14-3-3 protein zeta/delta.	[10]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of 14-3-3 protein zeta/delta.	[11]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of 14-3-3 protein zeta/delta.	[12]
Etretinate	DM2CZFA	Approved	Etretinate decreases the expression of 14-3-3 protein zeta/delta.	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of 14-3-3 protein zeta/delta.	[14]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of 14-3-3 protein zeta/delta.	[3]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of 14-3-3 protein zeta/delta.	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 14-3-3 protein zeta/delta.	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 14-3-3 protein zeta/delta.	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of 14-3-3 protein zeta/delta.	[19]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of 14-3-3 protein zeta/delta.	[20]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the expression of 14-3-3 protein zeta/delta.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of 14-3-3 protein zeta/delta.	[17]

References

• [1] Neurodevelopmental and neuropsychiatric behaviour defects arise from 14-3-3 deficiency. Mol Psychiatry. 2012 Apr;17(4):451-66. doi: 10.1038/mp.2011.158. Epub 2011 Nov 29.
• [2] 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.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [6] 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.
• [7] Quercetin acts via the G3BP1/YWHAZ axis to inhibit glycolysis and proliferation in oral squamous cell carcinoma. Toxicol Mech Methods. 2023 Feb;33(2):141-150. doi: 10.1080/15376516.2022.2103480. Epub 2022 Aug 9.
• [8] Arsenic trioxide (As(2)O(3)) induced apoptosis and its mechanisms in a human esophageal squamous carcinoma cell line. Chin Med J (Engl). 2002 Feb;115(2):280-5.
• [9] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [10] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [13] Consequences of the natural retinoid/retinoid X receptor ligands action in human breast cancer MDA-MB-231 cell line: Focus on functional proteomics. Toxicol Lett. 2017 Nov 5;281:26-34. doi: 10.1016/j.toxlet.2017.09.001. Epub 2017 Sep 5.
• [14] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [15] Gene expression preferentially regulated by tamoxifen in breast cancer cells and correlations with clinical outcome. Cancer Res. 2006 Jul 15;66(14):7334-40.
• [16] 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.
• [17] 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.
• [18] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [20] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [21] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.
• [22] Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol. 2011 Oct 17;24(10):1735-43. doi: 10.1021/tx2002806. Epub 2011 Aug 26.