Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3FAU4Y)

• DOT Name: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG)
• Synonyms: PI3-kinase subunit gamma; PI3K-gamma; PI3Kgamma; PtdIns-3-kinase subunit gamma; EC 2.7.1.137; EC 2.7.1.153; EC 2.7.1.154; Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma; PtdIns-3-kinase subunit p110-gamma; p110gamma; Phosphoinositide-3-kinase catalytic gamma polypeptide; Serine/threonine protein kinase PIK3CG; EC 2.7.11.1; p120-PI3K
• Gene Name: PIK3CG
• Related Disease: Immunodeficiency 97 with autoinflammation
• UniProt ID: PK3CG_HUMAN
• PDB ID: 1E8Y ; 1E8Z ; 1HE8 ; 2A4Z ; 2A5U ; 2CHW ; 2CHX ; 2CHZ ; 2V4L ; 3APC ; 3APD ; 3APF ; 3CSF ; 3CST ; 3DBS ; 3DPD ; 3ENE ; 3IBE ; 3L08 ; 3L13 ; 3L16 ; 3L17 ; 3L54 ; 3LJ3 ; 3MJW ; 3ML8 ; 3ML9 ; 3NZS ; 3NZU ; 3OAW ; 3P2B ; 3PRE ; 3PRZ ; 3PS6 ; 3QAQ ; 3QAR ; 3QJZ ; 3QK0 ; 3R7Q ; 3R7R ; 3S2A ; 3SD5 ; 3T8M ; 3TJP ; 3TL5 ; 3ZVV ; 3ZW3 ; 4ANU ; 4ANV ; 4ANW ; 4ANX ; 4AOF ; 4DK5 ; 4EZJ ; 4EZK ; 4EZL ; 4F1S ; 4FA6 ; 4FAD ; 4FHJ ; 4FHK ; 4FJY ; 4FJZ ; 4FLH ; 4FUL ; 4G11 ; 4GB9 ; 4HLE ; 4HVB ; 4J6I ; 4KZ0 ; 4KZC ; 4PS3 ; 4PS7 ; 4PS8 ; 4URK ; 4WWN ; 4WWO ; 4WWP ; 4XX5 ; 4XZ4 ; 5EDS ; 5G2N ; 5G55 ; 5JHA ; 5JHB ; 5KAE ; 5OQ4 ; 5T23 ; 6AUD ; 6C1S ; 6FH5 ; 6GQ7 ; 6T3B ; 6T3C ; 6XRL ; 6XRM ; 6XRN ; 7JWE ; 7JWZ ; 7JX0 ; 7KKE ; 7MEZ ; 7Z61 ; 8DP0
• EC Number: 2.7.1.137; 2.7.1.153; 2.7.1.154; 2.7.11.1
• Pfam ID: PF00454 ; PF00792 ; PF00794 ; PF00613 ; PF19710
• Sequence:
  MELENYKQPVVLREDNCRRRRRMKPRSAAASLSSMELIPIEFVLPTSQRKCKSPETALLH
  VAGHGNVEQMKAQVWLRALETSVAADFYHRLGPHHFLLLYQKKGQWYEIYDKYQVVQTLD
  CLRYWKATHRSPGQIHLVQRHPPSEESQAFQRQLTALIGYDVTDVSNVHDDELEFTRRGL
  VTPRMAEVASRDPKLYAMHPWVTSKPLPEYLWKKIANNCIFIVIHRSTTSQTIKVSPDDT
  PGAILQSFFTKMAKKKSLMDIPESQSEQDFVLRVCGRDEYLVGETPIKNFQWVRHCLKNG
  EEIHVVLDTPPDPALDEVRKEEWPLVDDCTGVTGYHEQLTIHGKDHESVFTVSLWDCDRK
  FRVKIRGIDIPVLPRNTDLTVFVEANIQHGQQVLCQRRTSPKPFTEEVLWNVWLEFSIKI
  KDLPKGALLNLQIYCGKAPALSSKASAESPSSESKGKVQLLYYVNLLLIDHRFLLRRGEY
  VLHMWQISGKGEDQGSFNADKLTSATNPDKENSMSISILLDNYCHPIALPKHQPTPDPEG
  DRVRAEMPNQLRKQLEAIIATDPLNPLTAEDKELLWHFRYESLKHPKAYPKLFSSVKWGQ
  QEIVAKTYQLLARREVWDQSALDVGLTMQLLDCNFSDENVRAIAVQKLESLEDDDVLHYL
  LQLVQAVKFEPYHDSALARFLLKRGLRNKRIGHFLFWFLRSEIAQSRHYQQRFAVILEAY
  LRGCGTAMLHDFTQQVQVIEMLQKVTLDIKSLSAEKYDVSSQVISQLKQKLENLQNSQLP
  ESFRVPYDPGLKAGALAIEKCKVMASKKKPLWLEFKCADPTALSNETIGIIFKHGDDLRQ
  DMLILQILRIMESIWETESLDLCLLPYGCISTGDKIGMIEIVKDATTIAKIQQSTVGNTG
  AFKDEVLNHWLKEKSPTEEKFQAAVERFVYSCAGYCVATFVLGIGDRHNDNIMITETGNL
  FHIDFGHILGNYKSFLGINKERVPFVLTPDFLFVMGTSGKKTSPHFQKFQDICVKAYLAL
  RHHTNLLIILFSMMLMTGMPQLTSKEDIEYIRDALTVGKNEEDAKKYFLDQIEVCRDKGW
  TVQFNWFLHLVLGIKQGEKHSA
• Function: Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation, activation, and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to GRK2 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.
• Tissue Specificity: Pancreas, skeletal muscle, liver and heart.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  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)
  Salmonella infection (hsa05132)
  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)
  Signaling by CSF1 (M-CSF) in myeloid cells (R-HSA-9680350)
  GPVI-mediated activation cascade (R-HSA-114604)
• BioCyc Pathway: MetaCyc:HS02818-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 97 with autoinflammation	DISCCAUQ	Moderate	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG) decreases the response to substance of Cisplatin.	[16]
Afimoxifene	DMFORDT	Phase 2	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG) decreases the response to substance of Afimoxifene.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[2]

15 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 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the activity of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[5]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[6]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the activity of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[7]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[8]
GDC0941	DM1YAK6	Phase 2	GDC0941 affects the activity of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[9]
GDC-0980/RG7422	DMF3MV1	Phase 2	GDC-0980/RG7422 decreases the activity of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[12]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the activity of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[4]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[14]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[14]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[14]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cordycepin	DM72Y01	Investigative	Cordycepin affects the binding of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PIK3CG).	[15]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] 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.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] Quercetin blocks airway epithelial cell chemokine expression. Am J Respir Cell Mol Biol. 2006 Nov;35(5):602-10. doi: 10.1165/rcmb.2006-0149OC. Epub 2006 Jun 22.
• [5] Arsenic trioxide reduces the expression of E2F1, cyclin E, and phosphorylation of PI3K signaling molecules in acute leukemia cells. Environ Toxicol. 2021 Sep;36(9):1785-1792. doi: 10.1002/tox.23299. Epub 2021 May 27.
• [6] Decitabine up-regulates S100A2 expression and synergizes with IFN-gamma to kill uveal melanoma cells. Clin Cancer Res. 2007 Sep 1;13(17):5219-25. doi: 10.1158/1078-0432.CCR-07-0816.
• [7] Resveratrol is a class IA phosphoinositide 3-kinase inhibitor. Biochem J. 2007 Sep 15;406(3):511-8. doi: 10.1042/BJ20070236.
• [8] Promyelocytic leukemia retinoid signaling targets regulate apoptosis,tissue factor and thrombomodulin expression. Haematologica. 2004 Mar;89(3):286-95.
• [9] The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008 Sep 25;51(18):5522-32. doi: 10.1021/jm800295d.
• [10] GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther. 2011 Dec;10(12):2426-36.
• [11] 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.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] 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.
• [15] Combination of Cordycepin and Apatinib Synergistically Inhibits NSCLC Cells by Down-Regulating VEGF/PI3K/Akt Signaling Pathway. Front Oncol. 2020 Sep 7;10:1732. doi: 10.3389/fonc.2020.01732. eCollection 2020.
• [16] A sensitized RNA interference screen identifies a novel role for the PI3K p110 isoform in medulloblastoma cell proliferation and chemoresistance. Mol Cancer Res. 2011 Jul;9(7):925-35. doi: 10.1158/1541-7786.MCR-10-0200. Epub 2011 Jun 7.
• [17] 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.