Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAMPX9V)

• DOT Name: Phosphatase and actin regulator 1 (PHACTR1)
• Gene Name: PHACTR1
• Related Disease:
  Coronary atherosclerosis
  Coronary heart disease
  Coronary ischemia
  Developmental and epileptic encephalopathy, 70
  Familial hypercholesterolemia
  Hypercholesterolemia, familial, 1
  Hyperlipidemia
  Intellectual disability
  Major depressive disorder
  Migraine disorder
  Neurodevelopmental disorder
  Vascular disease
  Acute myelogenous leukaemia
  Cardiovascular disease
  Obesity
  Stroke
  West syndrome
  Arteriosclerosis
  Atherosclerosis
  High blood pressure
• UniProt ID: PHAR1_HUMAN
• PDB ID: 6ZEE; 6ZEF; 6ZEG; 6ZEH; 6ZEI; 6ZEJ
• Pfam ID: PF02755
• Sequence:
  MDYPKMDYFLDVESAHRLLDVESAQRFFYSQGAQARRATLLLPPTLMAASSEDDIDRRPI
  RRVRSKSDTPYLAEARISFNLGAAEEVERLAAMRSDSLVPGTHTPPIRRRSKFANLGRIF
  KPWKWRKKKSEKFKHTSAALERKISMRQSREELIKRGVLKEIYDKDGELSISNEEDSLEN
  GQSLSSSQLSLPALSEMEPVPMPRDPCSYEVLQPSDIMDGPDPGAPVKLPCLPVKLSPPL
  PPKKVMICMPVGGPDLSLVSYTAQKSGQQGVAQHHHTVLPSQIQHQLQYGSHGQHLPSTT
  GSLPMHPSGCRMIDELNKTLAMTMQRLESSEQRVPCSTSYHSSGLHSGDGVTKAGPMGLP
  EIRQVPTVVIECDDNKENVPHESDYEDSSCLYTREEEEEEEDEDDDSSLYTSSLAMKVCR
  KDSLAIKLSNRPSKRELEEKNILPRQTDEERLELRQQIGTKLTRRLSQRPTAEELEQRNI
  LKPRNEQEEQEEKREIKRRLTRKLSQRPTVEELRERKILIRFSDYVEVADAQDYDRRADK
  PWTRLTAADKAAIRKELNEFKSTEMEVHELSRHLTRFHRP
• Function: Binds actin monomers (G actin) and plays a role in multiple processes including the regulation of actin cytoskeleton dynamics, actin stress fibers formation, cell motility and survival, formation of tubules by endothelial cells, and regulation of PPP1CA activity. Involved in the regulation of cortical neuron migration and dendrite arborization.
• Tissue Specificity: Detected in umbilical vein endothelial cells.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[1]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[1]
Coronary ischemia	DISDJJ5G	Strong	Genetic Variation	[2]
Developmental and epileptic encephalopathy, 70	DIS1ZJKT	Strong	Autosomal dominant	[3]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[4]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Genetic Variation	[4]
Hyperlipidemia	DIS61J3S	Strong	Genetic Variation	[1]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Migraine disorder	DISFCQTG	Strong	Genetic Variation	[7]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[5]
Vascular disease	DISVS67S	Strong	Genetic Variation	[8]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[9]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[10]
Obesity	DIS47Y1K	moderate	Genetic Variation	[11]
Stroke	DISX6UHX	moderate	Genetic Variation	[12]
West syndrome	DISLIAU9	Supportive	Autosomal dominant	[5]
Arteriosclerosis	DISK5QGC	Limited	Biomarker	[13]
Atherosclerosis	DISMN9J3	Limited	Biomarker	[13]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Phosphatase and actin regulator 1 (PHACTR1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Phosphatase and actin regulator 1 (PHACTR1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphatase and actin regulator 1 (PHACTR1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatase and actin regulator 1 (PHACTR1).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Phosphatase and actin regulator 1 (PHACTR1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Phosphatase and actin regulator 1 (PHACTR1).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phosphatase and actin regulator 1 (PHACTR1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phosphatase and actin regulator 1 (PHACTR1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphatase and actin regulator 1 (PHACTR1).	[22]
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of Phosphatase and actin regulator 1 (PHACTR1).	[23]

References

• [1] PHACTR1 gene polymorphism with the risk of coronary artery disease in Chinese Han population.Postgrad Med J. 2019 Feb;95(1120):67-71. doi: 10.1136/postgradmedj-2018-136298. Epub 2019 Feb 18.
• [2] Genome-wide association study in a Lebanese cohort confirms PHACTR1 as a major determinant of coronary artery stenosis.PLoS One. 2012;7(6):e38663. doi: 10.1371/journal.pone.0038663. Epub 2012 Jun 20.
• [3] Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Nov 15;367(20):1921-9. doi: 10.1056/NEJMoa1206524. Epub 2012 Oct 3.
• [4] PHACTR1 genotype predicts coronary artery disease in patients with familial hypercholesterolemia.J Clin Lipidol. 2018 Jul-Aug;12(4):966-971. doi: 10.1016/j.jacl.2018.04.012. Epub 2018 Apr 30.
• [5] De novo PHACTR1 mutations in West syndrome and their pathophysiological effects. Brain. 2018 Nov 1;141(11):3098-3114. doi: 10.1093/brain/awy246.
• [6] The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response.Transl Psychiatry. 2015 Apr 21;5(4):e553. doi: 10.1038/tp.2015.47.
• [7] Fibromuscular Dysplasia and Its Neurologic Manifestations: A Systematic Review.JAMA Neurol. 2019 Feb 1;76(2):217-226. doi: 10.1001/jamaneurol.2018.2848.
• [8] A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression.Cell. 2017 Jul 27;170(3):522-533.e15. doi: 10.1016/j.cell.2017.06.049.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] PHACTR1 and SLC22A3 gene polymorphisms are associated with reduced coronary artery disease risk in the male Chinese Han population.Oncotarget. 2017 Jan 3;8(1):658-663. doi: 10.18632/oncotarget.13506.
• [11] The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression.J Neural Transm (Vienna). 2019 Jan;126(1):35-45. doi: 10.1007/s00702-018-01966-x. Epub 2019 Jan 4.
• [12] Cervical Artery Dissection in Patients of African Ancestry.Cerebrovasc Dis. 2018;46(5-6):218-222. doi: 10.1159/000494704. Epub 2018 Dec 5.
• [13] PHACTR1 haplotypes are associated with carotid plaque presence and affect PHACTR1 mRNA expression in carotid plaque tissue.Gene. 2019 Aug 20;710:273-278. doi: 10.1016/j.gene.2019.06.020. Epub 2019 Jun 12.
• [14] 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.
• [15] 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.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [18] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [19] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] 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.
• [22] 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.
• [23] DNA Methylome Analysis of Saturated Aliphatic Aldehydes in Pulmonary Toxicity. Sci Rep. 2018 Jul 12;8(1):10497. doi: 10.1038/s41598-018-28813-z.