Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY2PROB)

• DOT Name: Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B)
• Synonyms: PI3K-C2-beta; PtdIns-3-kinase C2 subunit beta; EC 2.7.1.137; EC 2.7.1.154; C2-PI3K; Phosphoinositide 3-kinase-C2-beta
• Gene Name: PIK3C2B
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Diabetic kidney disease
  Esophageal squamous cell carcinoma
  Glioma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Systemic sclerosis
  Metastatic malignant neoplasm
  Small lymphocytic lymphoma
  Parkinson disease
  Neuroblastoma
  Small-cell lung cancer
  Stroke
• UniProt ID: P3C2B_HUMAN
• EC Number: 2.7.1.137; 2.7.1.154
• Pfam ID: PF00168 ; PF00454 ; PF00792 ; PF00794 ; PF00613 ; PF00787
• Sequence:
  MSSTQGNGEHWKSLESVGISRKELAMAEALQMEYDALSRLRHDKEENRAKQNADPSLISW
  DEPGVDFYSKPAGRRTDLKLLRGLSGSDPTLNYNSLSPQEGPPNHSTSQGPQPGSDPWPK
  GSLSGDYLYIFDGSDGGVSSSPGPGDIEGSCKKLSPPPLPPRASIWDTPPLPPRKGSPSS
  SKISQPSDINTFSLVEQLPGKLLEHRILEEEEVLGGGGQGRLLGSVDYDGINDAITRLNL
  KSTYDAEMLRDATRGWKEGRGPLDFSKDTSGKPVARSKTMPPQVPPRTYASRYGNRKNAT
  PGKNRRISAAPVGSRPHTVANGHELFEVSEERDEEVAAFCHMLDILRSGSDIQDYFLTGY
  VWSAVTPSPEHLGDEVNLKVTVLCDRLQEALTFTCNCSSTVDLLIYQTLCYTHDDLRNVD
  VGDFVLKPCGLEEFLQNKHALGSHEYIQYCRKFDIDIRLQLMEQKVVRSDLARTVNDDQS
  PSTLNYLVHLQERPVKQTISRQALSLLFDTYHNEVDAFLLADGDFPLKADRVVQSVKAIC
  NALAAVETPEITSALNQLPPCPSRMQPKIQKDPSVLAVRENREKVVEALTAAILDLVELY
  CNTFNADFQTAVPGSRKHDLVQEACHFARSLAFTVYATHRIPIIWATSYEDFYLSCSLSH
  GGKELCSPLQTRRAHFSKYLFHLIVWDQQICFPVQVNRLPRETLLCATLYALPIPPPGSS
  SEANKQRRVPEALGWVTTPLFNFRQVLTCGRKLLGLWPATQENPSARWSAPNFHQPDSVI
  LQIDFPTSAFDIKFTSPPGDKFSPRYEFGSLREEDQRKLKDIMQKESLYWLTDADKKRLW
  EKRYYCHSEVSSLPLVLASAPSWEWACLPDIYVLLKQWTHMNHQDALGLLHATFPDQEVR
  RMAVQWIGSLSDAELLDYLPQLVQALKYECYLDSPLVRFLLKRAVSDLRVTHYFFWLLKD
  GLKDSQFSIRYQYLLAALLCCCGKGLREEFNRQCWLVNALAKLAQQVREAAPSARQGILR
  TGLEEVKQFFALNGSCRLPLSPSLLVKGIVPRDCSYFNSNAVPLKLSFQNVDPLGENIRV
  IFKCGDDLRQDMLTLQMIRIMSKIWVQEGLDMRMVIFRCFSTGRGRGMVEMIPNAETLRK
  IQVEHGVTGSFKDRPLADWLQKHNPGEDEYEKAVENFIYSCAGCCVATYVLGICDRHNDN
  IMLKTTGHMFHIDFGRFLGHAQMFGNIKRDRAPFVFTSDMAYVINGGDKPSSRFHDFVDL
  CCQAYNLIRKHTHLFLNLLGLMLSCGIPELSDLEDLKYVYDALRPQDTEANATTYFTRLI
  ESSLGSVATKLNFFIHNLAQMKFTGSDDRLTLSFASRTHTLKSSGRISDVFLCRHEKIFH
  PNKGYIYVVKVMRENTHEATYIQRTFEEFQELHNKLRLLFPSSHLPSFPSRFVIGRSRGE
  AVAERRREELNGYIWHLIHAPPEVAECDLVYTFFHPLPRDEKAMGTSPAPKSSDGTWARP
  VGKVGGEVKLSISYKNNKLFIMVMHIRGLQLLQDGNDPDPYVKIYLLPDPQKTTKRKTKV
  ARKTCNPTYNEMLVYDGIPKGDLQQRELQLSVLSEQGFWENVLLGEVNIRLRELDLAQEK
  TGWFALGSRSHGTL
• Function: Phosphorylates PtdIns and PtdIns4P with a preference for PtdIns. Does not phosphorylate PtdIns(4,5)P2. May be involved in EGF and PDGF signaling cascades.
• Tissue Specificity: Expressed in columnar and transitional epithelia, mononuclear cells, and ganglion cells (at protein level). Widely expressed, with highest levels in thymus and placenta and lowest in peripheral blood, skeletal muscle and kidney.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  Salmonella infection (hsa05132)
• Reactome Pathway: Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
• BioCyc Pathway: MetaCyc:HS05725-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Diabetic kidney disease	DISJMWEY	Strong	Genetic Variation	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[7]
Prostate cancer	DISF190Y	Strong	Altered Expression	[8]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[8]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[1]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[10]
Parkinson disease	DISQVHKL	Disputed	Biomarker	[11]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[12]
Small-cell lung cancer	DISK3LZD	Limited	Altered Expression	[13]
Stroke	DISX6UHX	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B) affects the response to substance of Acetaminophen.	[30]
Methotrexate	DM2TEOL	Approved	Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B) affects the response to substance of Methotrexate.	[31]

15 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 beta (PIK3C2B).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[21]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[22]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[23]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[24]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[28]
Myricetin	DMTV4L0	Investigative	Myricetin decreases the expression of Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta (PIK3C2B).	[29]

References

• [1] Class II phosphoinositide 3-kinase C2 regulates a novel signaling pathway involved in breast cancer progression.Oncotarget. 2016 Apr 5;7(14):18325-45. doi: 10.18632/oncotarget.7761.
• [2] Genome-wide association study identifies new susceptibility loci for diabetic nephropathy in Korean patients with type 2 diabetes mellitus.Clin Genet. 2019 Jul;96(1):35-42. doi: 10.1111/cge.13538. Epub 2019 Apr 9.
• [3] Phosphatidylinositol 3-kinase-C2 inhibits cisplatin-mediated apoptosis via the Akt pathway in oesophageal squamous cell carcinoma.J Int Med Res. 2011;39(4):1319-32. doi: 10.1177/147323001103900419.
• [4] Identification of a novel population in high-grade oligodendroglial tumors not deleted on 1p/19q using array CGH.J Neurooncol. 2012 Sep;109(2):405-13. doi: 10.1007/s11060-012-0909-1. Epub 2012 Jul 24.
• [5] A class II phosphoinositide 3-kinase plays an indispensable role in hepatitis C virus replication.Biochem Biophys Res Commun. 2013 Oct 11;440(1):150-6. doi: 10.1016/j.bbrc.2013.09.048. Epub 2013 Sep 18.
• [6] Downregulation of class II phosphoinositide 3-kinase PI3K-C2 delays cell division and potentiates the effect of docetaxel on cancer cell growth.J Exp Clin Cancer Res. 2019 Nov 21;38(1):472. doi: 10.1186/s13046-019-1472-9.
• [7] Questioning the role of selected somatic PIK3C2B mutations in squamous non-small cell lung cancer oncogenesis.PLoS One. 2017 Oct 31;12(10):e0187308. doi: 10.1371/journal.pone.0187308. eCollection 2017.
• [8] Novel roles for class II Phosphoinositide 3-Kinase C2 in signalling pathways involved in prostate cancer cell invasion.Sci Rep. 2016 Mar 17;6:23277. doi: 10.1038/srep23277.
• [9] Increase in phosphotidylinositide-3 kinase activity by nitrotyrosylation of lysates of platelets from patients with systemic sclerosis.Biochim Biophys Acta. 2006 Jan;1760(1):32-7. doi: 10.1016/j.bbagen.2005.09.001. Epub 2005 Sep 20.
• [10] A seven-gene expression panel distinguishing clonal expansions of pre-leukemic and chronic lymphocytic leukemia B cells from normal B lymphocytes.Immunol Res. 2015 Dec;63(1-3):90-100. doi: 10.1007/s12026-015-8688-3.
• [11] Ropinirole alters gene expression profiles in SH-SY5Y cells: a whole genome microarray study.Braz J Med Biol Res. 2016 Feb;49(2):e4857. doi: 10.1590/1414-431X20154857. Epub 2016 Jan 19.
• [12] Intersectin 1 is required for neuroblastoma tumorigenesis.Oncogene. 2012 Nov 15;31(46):4828-34. doi: 10.1038/onc.2011.643. Epub 2012 Jan 23.
• [13] Two distinct phosphoinositide 3-kinases mediate polypeptide growth factor-stimulated PKB activation.EMBO J. 2002 Oct 1;21(19):5097-108. doi: 10.1093/emboj/cdf512.
• [14] Novel susceptibility genes were found in a targeted sequencing of stroke patients with or without depression in the Chinese Han population.J Affect Disord. 2019 Aug 1;255:1-9. doi: 10.1016/j.jad.2019.05.023. Epub 2019 May 13.
• [15] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [22] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [23] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [24] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [25] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [26] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [27] 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.
• [28] 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.
• [29] Potential role of nucleoside diphosphate kinase in myricetin-induced selective apoptosis in colon cancer HCT-15?cells. Food Chem Toxicol. 2018 Jun;116(Pt B):315-322. doi: 10.1016/j.fct.2018.04.053. Epub 2018 Apr 24.
• [30] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.
• [31] 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.