Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHSX3MX)

• DOT Name: Tribbles homolog 2 (TRIB2)
• Synonyms: TRB-2
• Gene Name: TRIB2
• Related Disease:
  Multiple sclerosis
  Nervous system disease
  Acute erythroid leukemia
  Acute monocytic leukemia
  Adult glioblastoma
  Advanced cancer
  Autoimmune disease
  Colorectal carcinoma
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Glioma
  Inflammatory bowel disease
  Lung cancer
  Lung neoplasm
  Narcolepsy
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Uveitis
  Vascular disease
  Lung adenocarcinoma
  Melanoma
  Metastatic melanoma
  Small lymphocytic lymphoma
  Small-cell lung cancer
  Lung carcinoma
  Adenocarcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
• UniProt ID: TRIB2_HUMAN
• PDB ID: 7UPM
• Pfam ID: PF00069
• Sequence:
  MNIHRSTPITIARYGRSRNKTQDFEELSSIRSAEPSQSFSPNLGSPSPPETPNLSHCVSC
  IGKYLLLEPLEGDHVFRAVHLHSGEELVCKVFDISCYQESLAPCFCLSAHSNINQITEII
  LGETKAYVFFERSYGDMHSFVRTCKKLREEEAARLFYQIASAVAHCHDGGLVLRDLKLRK
  FIFKDEERTRVKLESLEDAYILRGDDDSLSDKHGCPAYVSPEILNTSGSYSGKAADVWSL
  GVMLYTMLVGRYPFHDIEPSSLFSKIRRGQFNIPETLSPKAKCLIRSILRREPSERLTSQ
  EILDHPWFSTDFSVSNSAYGAKEVSDQLVPDVNMEENLDPFFN
• Function: Interacts with MAPK kinases and regulates activation of MAP kinases. Does not display kinase activity.
• Tissue Specificity: Highly expressed in peripheral blood leukocytes.

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[1]
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[2]
Acute erythroid leukemia	DISZFC1O	Strong	Biomarker	[3]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Autoimmune disease	DISORMTM	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[8]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[9]
Lung cancer	DISCM4YA	Strong	Altered Expression	[10]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[11]
Narcolepsy	DISLCNLI	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Altered Expression	[13]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[13]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[13]
Uveitis	DISV0RYS	Strong	Biomarker	[14]
Vascular disease	DISVS67S	Strong	Altered Expression	[15]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[16]
Melanoma	DIS1RRCY	moderate	Biomarker	[17]
Metastatic melanoma	DISSL43L	moderate	Altered Expression	[17]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[18]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[19]
Lung carcinoma	DISTR26C	Disputed	Altered Expression	[10]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[20]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[10]
Liver cancer	DISDE4BI	Limited	Biomarker	[10]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Tribbles homolog 2 (TRIB2) affects the response to substance of Etoposide.	[43]
Mitomycin	DMH0ZJE	Approved	Tribbles homolog 2 (TRIB2) affects the response to substance of Mitomycin.	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Tribbles homolog 2 (TRIB2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tribbles homolog 2 (TRIB2).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tribbles homolog 2 (TRIB2).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tribbles homolog 2 (TRIB2).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tribbles homolog 2 (TRIB2).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tribbles homolog 2 (TRIB2).	[25]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Tribbles homolog 2 (TRIB2).	[26]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tribbles homolog 2 (TRIB2).	[27]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tribbles homolog 2 (TRIB2).	[28]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tribbles homolog 2 (TRIB2).	[29]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Tribbles homolog 2 (TRIB2).	[30]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Tribbles homolog 2 (TRIB2).	[31]
Irinotecan	DMP6SC2	Approved	Irinotecan affects the expression of Tribbles homolog 2 (TRIB2).	[32]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Tribbles homolog 2 (TRIB2).	[33]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Tribbles homolog 2 (TRIB2).	[34]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Tribbles homolog 2 (TRIB2).	[35]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Tribbles homolog 2 (TRIB2).	[36]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Tribbles homolog 2 (TRIB2).	[37]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tribbles homolog 2 (TRIB2).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tribbles homolog 2 (TRIB2).	[40]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tribbles homolog 2 (TRIB2).	[41]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Tribbles homolog 2 (TRIB2).	[42]

References

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• [4] Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells.Sci Signal. 2018 Sep 25;11(549):eaat7951. doi: 10.1126/scisignal.aat7951.
• [5] Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma.CNS Neurosci Ther. 2020 Mar;26(3):297-308. doi: 10.1111/cns.13197. Epub 2019 Jul 18.
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• [20] miR-511 and miR-1297 inhibit human lung adenocarcinoma cell proliferation by targeting oncogene TRIB2.PLoS One. 2012;7(10):e46090. doi: 10.1371/journal.pone.0046090. Epub 2012 Oct 5.
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• [26] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [27] 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.
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• [34] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [35] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [36] 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.
• [37] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [38] 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.
• [39] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [40] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [41] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [42] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
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