Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFBU4GD)

• DOT Name: Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A)
• Synonyms: PI3K-C2-alpha; PtdIns-3-kinase C2 subunit alpha; EC 2.7.1.137; EC 2.7.1.153; EC 2.7.1.154; Phosphoinositide 3-kinase-C2-alpha
• Gene Name: PIK3C2A
• Related Disease:
  Abetalipoproteinemia
  Acute myocardial infarction
  Advanced cancer
  Anemia
  Breast cancer
  Breast carcinoma
  Coenzyme Q10 deficiency
  Coronary atherosclerosis
  Coronary heart disease
  Distal myopathy
  Duchenne muscular dystrophy
  Hepatocellular carcinoma
  Hyperphosphatemia
  Leukopenia
  McLeod neuroacanthocytosis syndrome
  Muscular dystrophy
  Myeloid leukaemia
  Myopathy
  Neoplasm
  Oculocerebrodental syndrome
  Systemic lupus erythematosus
  Thrombocytopenia
  Gastrointestinal stromal tumour
  Bipolar disorder
  Kaposi sarcoma
  Mental disorder
  Non-insulin dependent diabetes
  Psychotic disorder
  Schizophrenia
• UniProt ID: P3C2A_HUMAN
• PDB ID: 2AR5; 2IWL; 2REA; 2RED; 6BTY; 6BTZ; 6BU0; 6BUB
• EC Number: 2.7.1.137; 2.7.1.153; 2.7.1.154
• Pfam ID: PF00168 ; PF00454 ; PF00792 ; PF00794 ; PF00613 ; PF00787
• Sequence:
  MAQISSNSGFKECPSSHPEPTRAKDVDKEEALQMEAEALAKLQKDRQVTDNQRGFELSSS
  TRKKAQVYNKQDYDLMVFPESDSQKRALDIDVEKLTQAELEKLLLDDSFETKKTPVLPVT
  PILSPSFSAQLYFRPTIQRGQWPPGLPGPSTYALPSIYPSTYSKQAAFQNGFNPRMPTFP
  STEPIYLSLPGQSPYFSYPLTPATPFHPQGSLPIYRPVVSTDMAKLFDKIASTSEFLKNG
  KARTDLEITDSKVSNLQVSPKSEDISKFDWLDLDPLSKPKVDNVEVLDHEEEKNVSSLLA
  KDPWDAVLLEERSTANCHLERKVNGKSLSVATVTRSQSLNIRTTQLAKAQGHISQKDPNG
  TSSLPTGSSLLQEVEVQNEEMAAFCRSITKLKTKFPYTNHRTNPGYLLSPVTAQRNICGE
  NASVKVSIDIEGFQLPVTFTCDVSSTVEIIIMQALCWVHDDLNQVDVGSYVLKVCGQEEV
  LQNNHCLGSHEHIQNCRKWDTEIRLQLLTFSAMCQNLARTAEDDETPVDLNKHLYQIEKP
  CKEAMTRHPVEELLDSYHNQVELALQIENQHRAVDQVIKAVRKICSALDGVETLAITESV
  KKLKRAVNLPRSKTADVTSLFGGEDTSRSSTRGSLNPENPVQVSINQLTAAIYDLLRLHA
  NSGRSPTDCAQSSKSVKEAWTTTEQLQFTIFAAHGISSNWVSNYEKYYLICSLSHNGKDL
  FKPIQSKKVGTYKNFFYLIKWDELIIFPIQISQLPLESVLHLTLFGILNQSSGSSPDSNK
  QRKGPEALGKVSLPLFDFKRFLTCGTKLLYLWTSSHTNSVPGTVTKKGYVMERIVLQVDF
  PSPAFDIIYTTPQVDRSIIQQHNLETLENDIKGKLLDILHKDSSLGLSKEDKAFLWEKRY
  YCFKHPNCLPKILASAPNWKWVNLAKTYSLLHQWPALYPLIALELLDSKFADQEVRSLAV
  TWIEAISDDELTDLLPQFVQALKYEIYLNSSLVQFLLSRALGNIQIAHNLYWLLKDALHD
  VQFSTRYEHVLGALLSVGGKRLREELLKQTKLVQLLGGVAEKVRQASGSARQVVLQRSME
  RVQSFFQKNKCRLPLKPSLVAKELNIKSCSFFSSNAVPLKVTMVNADPMGEEINVMFKVG
  EDLRQDMLALQMIKIMDKIWLKEGLDLRMVIFKCLSTGRDRGMVELVPASDTLRKIQVEY
  GVTGSFKDKPLAEWLRKYNPSEEEYEKASENFIYSCAGCCVATYVLGICDRHNDNIMLRS
  TGHMFHIDFGKFLGHAQMFGSFKRDRAPFVLTSDMAYVINGGEKPTIRFQLFVDLCCQAY
  NLIRKQTNLFLNLLSLMIPSGLPELTSIQDLKYVRDALQPQTTDAEATIFFTRLIESSLG
  SIATKFNFFIHNLAQLRFSGLPSNDEPILSFSPKTYSFRQDGRIKEVSVFTYHKKYNPDK
  HYIYVVRILREGQIEPSFVFRTFDEFQELHNKLSIIFPLWKLPGFPNRMVLGRTHIKDVA
  AKRKIELNSYLQSLMNASTDVAECDLVCTFFHPLLRDEKAEGIARSADAGSFSPTPGQIG
  GAVKLSISYRNGTLFIMVMHIKDLVTEDGADPNPYVKTYLLPDNHKTSKRKTKISRKTRN
  PTFNEMLVYSGYSKETLRQRELQLSVLSAESLRENFFLGGVTLPLKDFNLSKETVKWYQL
  TAATYL
• Function: Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers. Has a role in several intracellular trafficking events. Functions in insulin signaling and secretion. Required for translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane and glucose uptake in response to insulin-mediated RHOQ activation. Regulates insulin secretion through two different mechanisms: involved in glucose-induced insulin secretion downstream of insulin receptor in a pathway that involves AKT1 activation and TBC1D4/AS160 phosphorylation, and participates in the late step of insulin granule exocytosis probably in insulin granule fusion. Synthesizes PtdIns3P in response to insulin signaling. Functions in clathrin-coated endocytic vesicle formation and distribution. Regulates dynamin-independent endocytosis, probably by recruiting EEA1 to internalizing vesicles. In neurosecretory cells synthesizes PtdIns3P on large dense core vesicles. Participates in calcium induced contraction of vascular smooth muscle by regulating myosin light chain (MLC) phosphorylation through a mechanism involving Rho kinase-dependent phosphorylation of the MLCP-regulatory subunit MYPT1. May play a role in the EGF signaling cascade. May be involved in mitosis and UV-induced damage response. Required for maintenance of normal renal structure and function by supporting normal podocyte function. Involved in the regulation of ciliogenesis and trafficking of ciliary components.
• Tissue Specificity: Expressed in columnar and transitional epithelia, mononuclear cells, smooth muscle cells, and endothelial cells lining capillaries and small venules (at protein level). Ubiquitously expressed, with highest levels in heart, placenta and ovary, and lowest levels in the kidney. Detected at low levels in islets of Langerhans from type 2 diabetes mellitus individuals.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  Synthesis of PIPs at the Golgi membrane (R-HSA-1660514)
  Synthesis of PIPs at the early endosome membrane (R-HSA-1660516)
  Synthesis of PIPs at the late endosome membrane (R-HSA-1660517)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
• BioCyc Pathway: MetaCyc:HS00315-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abetalipoproteinemia	DISMSS7T	Strong	Altered Expression	[1]
Acute myocardial infarction	DISE3HTG	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Anemia	DISTVL0C	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Coenzyme Q10 deficiency	DIS1HGDF	Strong	Altered Expression	[6]
Coronary atherosclerosis	DISKNDYU	Strong	Altered Expression	[2]
Coronary heart disease	DIS5OIP1	Strong	Altered Expression	[2]
Distal myopathy	DIS7F5R0	Strong	Altered Expression	[7]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Hyperphosphatemia	DISHW3R3	Strong	Biomarker	[4]
Leukopenia	DISJMBMM	Strong	Altered Expression	[9]
McLeod neuroacanthocytosis syndrome	DISA8FUX	Strong	Genetic Variation	[10]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[11]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[12]
Myopathy	DISOWG27	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Oculocerebrodental syndrome	DIS9OECG	Strong	Autosomal recessive	[13]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[14]
Thrombocytopenia	DISU61YW	Strong	Altered Expression	[9]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[15]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[16]
Kaposi sarcoma	DISC1H1Z	Limited	Biomarker	[17]
Mental disorder	DIS3J5R8	Limited	Genetic Variation	[16]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[18]
Psychotic disorder	DIS4UQOT	Limited	Genetic Variation	[16]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A) increases the Liver injury ADR of Ethanol.	[39]
Paclitaxel	DMLB81S	Approved	Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A) affects the response to substance of Paclitaxel.	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[22]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[24]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[25]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[26]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[27]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[24]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[28]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[29]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[30]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[36]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[23]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[33]
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A).	[38]

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