Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT481GQ4)

• DOT Name: GSK-3-binding protein FRAT2 (FRAT2)
• Synonyms: Frequently rearranged in advanced T-cell lymphomas 2; FRAT-2
• Gene Name: FRAT2
• Related Disease:
  Advanced cancer
  Gastric cancer
  Leukemia
  Stomach cancer
• UniProt ID: FRAT2_HUMAN
• Pfam ID: PF05350
• Sequence:
  MPCRREEEEEAGEEAEGEEEEDDSFLLLQQSVTLGSSGEVDRLVAQIGETLQLDAAQDSP
  ASPCAPPGVPLRAPGPLAAAVPADKARPPAVPLLLPPASAETVGPAPSGALRCALGDRGR
  VRGRAAPYCVAEVAAGPSALPGPCRRGWLRDAVTSRRLQQRRWTQAGARAGDDDPHRLLQ
  QLVLSGNLIKEAVRRLQRAVAAVAATGPASAPGPGGGRSGPDRIALQPSGSLL
• Function: Positively regulates the Wnt signaling pathway by stabilizing beta-catenin through the association with GSK-3.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Pathways in cancer (hsa05200)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  Beta-catenin phosphorylation cascade (R-HSA-196299)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[1]
Leukemia	DISNAKFL	Strong	Altered Expression	[2]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[1]

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 GSK-3-binding protein FRAT2 (FRAT2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of GSK-3-binding protein FRAT2 (FRAT2).	[8]

11 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 GSK-3-binding protein FRAT2 (FRAT2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of GSK-3-binding protein FRAT2 (FRAT2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GSK-3-binding protein FRAT2 (FRAT2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GSK-3-binding protein FRAT2 (FRAT2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of GSK-3-binding protein FRAT2 (FRAT2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of GSK-3-binding protein FRAT2 (FRAT2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of GSK-3-binding protein FRAT2 (FRAT2).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of GSK-3-binding protein FRAT2 (FRAT2).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of GSK-3-binding protein FRAT2 (FRAT2).	[13]
Calphostin C	DM9X2D0	Terminated	Calphostin C affects the expression of GSK-3-binding protein FRAT2 (FRAT2).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of GSK-3-binding protein FRAT2 (FRAT2).	[15]

References

• [1] FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are up-regulated in gastric cancer.Int J Oncol. 2001 Aug;19(2):311-5. doi: 10.3892/ijo.19.2.311.
• [2] Frat2 mediates the oncogenic activation of Rac by MLL fusions.Blood. 2012 Dec 6;120(24):4819-28. doi: 10.1182/blood-2012-05-432534. Epub 2012 Oct 16.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.
• [10] 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.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] 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.
• [13] 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.
• [14] Targeting the beta-catenin/TCF transcriptional complex in the treatment of multiple myeloma. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7516-21. doi: 10.1073/pnas.0610299104. Epub 2007 Apr 23.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.