Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4LNXJU)

• DOT Name: Phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5)
• Synonyms: PI3-kinase regulatory subunit 5; PI3-kinase p101 subunit; Phosphatidylinositol 4,5-bisphosphate 3-kinase regulatory subunit; PtdIns-3-kinase regulatory subunit; Protein FOAP-2; PtdIns-3-kinase p101; p101-PI3K
• Gene Name: PIK3R5
• Related Disease:
  Cerebellar ataxia
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Breast carcinoma
  Carcinoma
  Hypothyroidism
  Neoplasm
  T-cell lymphoma
  Inflammation
  Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
  Hepatitis
• UniProt ID: PI3R5_HUMAN
• Pfam ID: PF10486
• Sequence:
  MQPGATTCTEDRIQHALERCLHGLSLSRRSTSWSAGLCLNCWSLQELVSRDPGHFLILLE
  QILQKTREVQEKGTYDLLTPLALLFYSTVLCTPHFPPDSDLLLKAASTYHRFLTWPVPYC
  SICQELLTFIDAELKAPGISYQRLVRAEQGLPIRSHRSSTVTVLLLNPVEVQAEFLAVAN
  KLSTPGHSPHSAYTTLLLHAFQATFGAHCDVPGLHCRLQAKTLAELEDIFTETAEAQELA
  SGIGDAAEARRWLRTKLQAVGEKAGFPGVLDTAKPGKLHTIPIPVARCYTYSWSQDSFDI
  LQEILLKEQELLQPGILGDDEEEEEEEEEVEEDLETDGHCAERDSLLSTSSLASHDSTLS
  LASSQASGPALSRHLLTSFVSGLSDGMDSGYVEDSEESSSEWPWRRGSQERRGHRRPGQK
  FIRIYKLFKSTSQLVLRRDSRSLEGSSDTALPLRRAGSLCSPLDEPVSPPSRAQRSRSLP
  QPKLGTQLPSWLLAPASRPQRRRPFLSGDEDPKASTLRVVVFGSDRISGKVARAYSNLRR
  LENNRPLLTRFFKLQFFYVPVKRSHGTSPGACPPPRSQTPSPPTDSPRHASPGELGTTPW
  EESTNDISHYLGMLDPWYERNVLGLMHLPPEVLCQQSLKAEAQALEGSPTQLPILADMLL
  YYCRFAARPVLLQVYQTELTFITGEKTTEIFIHSLELGHSAATRAIKASGPGSKRLGIDG
  DREAVPLTLQIIYSKGAISGRSRWSNLEKVCTSVNLNKACRKQEELDSSMEALTLNLTEV
  VKRQNSKSKKGFNQISTSQIKVDKVQIIGSNSCPFAVCLDQDERKILQSVVRCEVSPCYK
  PEKSDLSSPPQTPPDLPAQAAPDLCSLLCLPIMTFSGALP
• Function: Regulatory subunit of the PI3K gamma complex. Required for recruitment of the catalytic subunit to the plasma membrane via interaction with beta-gamma G protein dimers. Required for G protein-mediated activation of PIK3CG.
• Tissue Specificity: Ubiquitously expressed with high expression in fetal brain compared to adult brain. Abundant expression is observed in cerebellum, cerebral cortex, cerebral meninges, and vermis cerebelli.
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Chemokine sig.ling pathway (hsa04062)
  Phospholipase D sig.ling pathway (hsa04072)
  PI3K-Akt sig.ling pathway (hsa04151)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Apelin sig.ling pathway (hsa04371)
  Platelet activation (hsa04611)
  Cholinergic sy.pse (hsa04725)
  Oxytocin sig.ling pathway (hsa04921)
  Toxoplasmosis (hsa05145)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
• Reactome Pathway:
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
  G beta (R-HSA-392451)
  Erythropoietin activates Phosphoinositide-3-kinase (PI3K) (R-HSA-9027276)
  GPVI-mediated activation cascade (R-HSA-114604)
• BioCyc Pathway: MetaCyc:HS13887-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar ataxia	DIS9IRAV	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[6]
Inflammation	DISJUQ5T	moderate	Biomarker	[7]
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	DIS84UUI	Supportive	Autosomal recessive	[1]
Hepatitis	DISXXX35	Limited	Biomarker	[8]

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 Phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5).	[9]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5).	[15]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5).	[15]

References

• [1] A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia. Hum Mutat. 2012 Feb;33(2):351-4. doi: 10.1002/humu.21650. Epub 2011 Dec 8.
• [2] Differential roles for the p101 and p84 regulatory subunits of PI3K in tumor growth and metastasis.Oncogene. 2012 May 3;31(18):2350-61. doi: 10.1038/onc.2011.414. Epub 2011 Sep 26.
• [3] Atheroprotective vaccination with MHC-II-restricted ApoB peptides induces peritoneal IL-10-producing CD4 T cells.Am J Physiol Heart Circ Physiol. 2017 Apr 1;312(4):H781-H790. doi: 10.1152/ajpheart.00798.2016. Epub 2017 Jan 13.
• [4] Analysis of molecular markers as predictive factors of lymph node involvement in breast carcinoma.Oncol Lett. 2017 Jan;13(1):488-496. doi: 10.3892/ol.2016.5438. Epub 2016 Nov 28.
• [5] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [6] Overexpression of p101 activates PI3Kgamma signaling in T cells and contributes to cell survival.Oncogene. 2007 Oct 25;26(49):7049-57. doi: 10.1038/sj.onc.1210504. Epub 2007 May 7.
• [7] Interleukin 1 and nuclear factor-kappaB polymorphisms in ankylosing spondylitis in Canada and Korea.J Rheumatol. 2005 Oct;32(10):1907-10.
• [8] Transcriptome analysis revealed ameliorative effect of probiotic Lactobacillus johnsonii BS15 against subclinical necrotic enteritis induced hepatic inflammation in broilers.Microb Pathog. 2019 Jul;132:201-207. doi: 10.1016/j.micpath.2019.05.011. Epub 2019 May 8.
• [9] 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.
• [10] 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.
• [11] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [13] 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.
• [14] 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.
• [15] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.