Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWMX2A8)

• DOT Name: Phosphatase and actin regulator 2 (PHACTR2)
• Gene Name: PHACTR2
• Related Disease:
  Hypospadias
  Non-small-cell lung cancer
  Inflammatory bowel disease
  Parkinson disease
• UniProt ID: PHAR2_HUMAN
• Pfam ID: PF02755
• Sequence:
  MDNAVDGLDKASIANSDGPTAGSQTPPFKRKGKLSTIGKIFKPWKWRKKKTSDKFRETSA
  VLERKISTRQSREELIRRGVLKELPDQDGDVTVNFENSNGHMIPIGEESTREENVVKSEE
  GNGSVSEKTPPLEEQAEDKKENTENHSETPAAPALPPSAPPKPRPKPKPKKSPVPPKGAT
  AGASHKGDEVPPIKKNTKAPGKQAPVPPPKPASRNTTREAAGSSHSKKTTGSKASASPST
  SSTSSRPKASKETVSSKAGTVGTTKGKRKTDKQPITSHLSSDTTTSGTSDLKGEPAETRV
  ESFKLEQTVPGAEEQNTGKFKSMVPPPPVAPAPSPLAPPLPLEDQCITASDTPVVLVSVG
  ADLPVSALDPSQLLWAEEPTNRTTLYSGTGLSVNRENAKCFTTKEELGKTVPQLLTPGLM
  GESSESFSASEDEGHREYQANDSDSDGPILYTDDEDEDEDEDGSGESALASKIRRRDTLA
  IKLGNRPSKKELEDKNILQRTSEEERQEIRQQIGTKLVRRLSQRPTTEELEQRNILKQKN
  EEEEQEAKMELKRRLSRKLSLRPTVAELQARRILRFNEYVEVTDSPDYDRRADKPWARLT
  PADKAAIRKELNEFKSTEMEVHEESRQFTRFHRP
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypospadias	DIS48CCP	Strong	Genetic Variation	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[2]
Inflammatory bowel disease	DISGN23E	moderate	Genetic Variation	[3]
Parkinson disease	DISQVHKL	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Phosphatase and actin regulator 2 (PHACTR2) affects the response to substance of Methotrexate.	[24]

3 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 Phosphatase and actin regulator 2 (PHACTR2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphatase and actin regulator 2 (PHACTR2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Phosphatase and actin regulator 2 (PHACTR2).	[18]

17 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 Phosphatase and actin regulator 2 (PHACTR2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phosphatase and actin regulator 2 (PHACTR2).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[13]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[17]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[19]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Phosphatase and actin regulator 2 (PHACTR2).	[23]

References

• [1] Genome-wide association analyses identify variants in developmental genes associated with hypospadias.Nat Genet. 2014 Sep;46(9):957-63. doi: 10.1038/ng.3063. Epub 2014 Aug 10.
• [2] Association between polymorphisms in CHRNA3 and PHACTR2 gene and environment and NSCLC risk in Chinese population.Acta Biochim Pol. 2014;61(4):765-8. Epub 2014 Nov 14.
• [3] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [4] Phactr2 and Parkinson's disease.Neurosci Lett. 2009 Mar 27;453(1):9-11. doi: 10.1016/j.neulet.2009.02.009. Epub 2009 Feb 10.
• [5] 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.
• [6] 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.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [14] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] 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.
• [19] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [20] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [21] 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.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.