Target Information
| Target General Information | Top | |||||
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| Target ID |
T94131
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| Target Name |
HUMAN PI3-kinase gamma (PIK3CG)
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| Synonyms |
p120-PI3K; p110gamma; Serine/threonine protein kinase PIK3CG; PtdIns-3-kinase subunit p110-gamma; PtdIns-3-kinase subunit gamma; PtdIns-3-kinase p110; Phosphoinositol-3 kinase; Phosphoinositide-3-kinase catalytic gamma polypeptide; Phosphoinositide 3-Kinase gamma; Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, gamma isoform; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform; Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma; PI3Kgamma; PI3K-gamma; PI3K; PI3-kinase subunit gamma; PI3-kinase p110 subunit gamma
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| Gene Name |
PIK3CG
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| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Follicular lymphoma [ICD-11: 2A80] | |||||
| 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 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.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.1.153
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| Sequence |
MELENYKQPVVLREDNCRRRRRMKPRSAAASLSSMELIPIEFVLPTSQRKCKSPETALLH
VAGHGNVEQMKAQVWLRALETSVAADFYHRLGPHHFLLLYQKKGQWYEIYDKYQVVQTLD CLRYWKATHRSPGQIHLVQRHPPSEESQAFQRQLTALIGYDVTDVSNVHDDELEFTRRGL VTPRMAEVASRDPKLYAMHPWVTSKPLPEYLWKKIANNCIFIVIHRSTTSQTIKVSPDDT PGAILQSFFTKMAKKKSLMDIPESQSEQDFVLRVCGRDEYLVGETPIKNFQWVRHCLKNG EEIHVVLDTPPDPALDEVRKEEWPLVDDCTGVTGYHEQLTIHGKDHESVFTVSLWDCDRK FRVKIRGIDIPVLPRNTDLTVFVEANIQHGQQVLCQRRTSPKPFTEEVLWNVWLEFSIKI KDLPKGALLNLQIYCGKAPALSSKASAESPSSESKGKVQLLYYVNLLLIDHRFLLRRGEY VLHMWQISGKGEDQGSFNADKLTSATNPDKENSMSISILLDNYCHPIALPKHQPTPDPEG DRVRAEMPNQLRKQLEAIIATDPLNPLTAEDKELLWHFRYESLKHPKAYPKLFSSVKWGQ QEIVAKTYQLLARREVWDQSALDVGLTMQLLDCNFSDENVRAIAVQKLESLEDDDVLHYL LQLVQAVKFEPYHDSALARFLLKRGLRNKRIGHFLFWFLRSEIAQSRHYQQRFAVILEAY LRGCGTAMLHDFTQQVQVIEMLQKVTLDIKSLSAEKYDVSSQVISQLKQKLENLQNSQLP ESFRVPYDPGLKAGALAIEKCKVMASKKKPLWLEFKCADPTALSNETIGIIFKHGDDLRQ DMLILQILRIMESIWETESLDLCLLPYGCISTGDKIGMIEIVKDATTIAKIQQSTVGNTG AFKDEVLNHWLKEKSPTEEKFQAAVERFVYSCAGYCVATFVLGIGDRHNDNIMITETGNL FHIDFGHILGNYKSFLGINKERVPFVLTPDFLFVMGTSGKKTSPHFQKFQDICVKAYLAL RHHTNLLIILFSMMLMTGMPQLTSKEDIEYIRDALTVGKNEEDAKKYFLDQIEVCRDKGW TVQFNWFLHLVLGIKQGEKHSA Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Drugs in Phase 2 Trial | [+] 1 | + | ||||
| 1 | Duvelisib | Drug Info | Approved | Follicular lymphoma | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | Duvelisib | Drug Info | [1] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Copanlisib | Ligand Info | |||||
| Structure Description | X-ray structure of PI3Kinase Gamma in complex with Copanlisib | PDB:5G2N | ||||
| Method | X-ray diffraction | Resolution | 2.68 Å | Mutation | No | [3] |
| PDB Sequence |
SEESQAFQRQ
153 LTALIGYDVT163 DVSNVHDDEL173 EFTRRGLVTP183 RMAEVASRDP193 KLYAMHPWVT 203 SKPLPEYLWK213 KIANNCIFIV223 IHRSTTSQTI233 KVSPDDTPGA243 ILQSFFTKMD 269 FVLRVCGRDE279 YLVGETPIKN289 FQWVRHCLKN299 GEEIHVVLDT309 PPDPALDEVR 319 KEEWCDRKFR362 VKIRGIDIPV372 LDLTVFVEAN386 IQHGQQVLCQ396 RRTSPKPFTE 406 EVLWNVWLEF416 SIKIKDLPKG426 ALLNLQIYCQ459 LLYYVNLLLI469 DHRFLLRRGE 479 YVLHMWQISG489 FNADKLTSAT506 NPDKENSMSI516 SILLDNHPIA528 AEMPNQLRKQ 554 LEAIIATDPL564 NPLTAEDKEL574 LWHFRYESLK584 HPKAYPKLFS594 SVKWGQQEIV 604 AKTYQLLARR614 EVWDQSALDV624 GLTMQLLDCN634 FSDENVRAIA644 VQKLESLEDD 654 DVLHYLLQLV664 QAVKFEPYHD674 SALARFLLKR684 GLRNKRIGHF694 LFWFLRSEIA 704 QSRHYQQRFA714 VILEAYLRGC724 GTAMLHDFTQ734 QVQVIEMLQK744 VTLDIKSLSA 754 EKYDVSSQVI764 SQLKQKLENL774 QNSQLPESFR784 VPYDPGLKAG794 ALAIEKCKVM 804 ASKKKPLWLE814 FKCADPTALS824 NETIGIIFKH834 GDDLRQDMLI844 LQILRIMESI 854 WETESLDLCL864 LPYGCISTGD874 KIGMIEIVKD884 ATTIAKIQTG900 AFKDEVLNHW 910 LKEKSPTEEK920 FQAAVERFVY930 SCAGYCVATF940 VLGIGDRHND950 NIMITETGNL 960 FHIDFGHIER982 VPFVLTPDFL992 FVMGTSGKKT1002 SPHFQKFQDI1012 CVKAYLALRH 1022 HTNLLIILFS1032 MMLMTGMPDI1048 EYIRDALTVG1058 KNEEDAKKYF1068 LDQIEVCRDK 1078 GWTVQFNWFL1088 HLV
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LYS800
4.669
LYS802
3.261
MET804
4.039
TRP812
3.425
GLU814
4.811
ILE831
3.579
LYS833
3.331
ASP836
3.211
LEU838
3.526
ASP841
3.381
TYR867
3.654
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| Ligand Name: Buparlisib | Ligand Info | |||||
| Structure Description | Crystal Structure of PI3K gamma with 5-(2,4-dimorpholinopyrimidin-6-yl)-4-(trifluoromethyl)pyridin-2-amine | PDB:3SD5 | ||||
| Method | X-ray diffraction | Resolution | 3.20 Å | Mutation | No | [4] |
| PDB Sequence |
SEESQAFQRQ
153 LTALIGYDVT163 DVSNVHDDEL173 EFTRRGLVTP183 RMAEVASRDP193 KLYAMHPWVT 203 SKPLPEYLWK213 NCIFIVIHRS227 TTSQTIKVSP237 DDTPGAILQS247 FFTKMQDFVL 272 RVCGRDEYLV282 GETPIKNFQW292 VRHCLKNGEE302 IHVVLDTPPD312 PALDEVRKCD 358 RKFRVKIRGI368 DIPVLTVFVE384 ANIQHGQQVL394 CQRRTSPKPF404 TEEVLWNVWL 414 EFSIKIKDLP424 KGALLNLQIY434 CVRLLYYVNL466 LLIDHRFLLR476 RGEYVLHMWQ 486 ISGNADKLTS504 ATNPDKENSM514 SISILLDNMP548 NQLRKQLEAI558 IATDPLNPLT 568 AEDKELLWHF578 RYESLKHPKA588 YPKLFSSVKW598 GQQEIVAKTY608 QLLARREVWD 618 QSALDVGLTM628 QLLDCNFSDE638 NVRAIAVQKL648 ESLEDDDVLH658 YLLQLVQAVK 668 FEPYHDSALA678 RFLLKRGLRN688 KRIGHFLFWF698 LRSEIAQSRH708 YQQRFAVILE 718 AYLRGCGTAM728 LHDFTQQVQV738 IEMLQKVTLD748 IKSLSAEKYD758 VSSQVISQLK 768 QKLENLQNSQ778 LPESFRVPYD788 PGLKAGALAI798 EKCKVMASKK808 KPLWLEFKCA 818 DPTANETIGI830 IFKHGDDLRQ840 DMLILQILRI850 MESIWETESL860 DLCLLPYGCI 870 STGDKIGMIE880 IVKDATTIAK890 IQQSTVTGAF902 KDEVLNHWLK912 EKSPTEEKFQ 922 AAVERFVYSC932 AGYCVATFVL942 GIGDRHNDNI952 MITETGNLFH962 IDFGHILGNR 982 VPFVLTPDFL992 FVMGTSKTSP1004 HFQKFQDICV1014 KAYLALRHHT1024 NLLIILFSMM 1034 LMTGMQLTSK1045 EDIEYIRDAL1055 TVGKNEEDAK1065 KYFLDQIEVC1075 RDKGWTVQFN 1085 WFLHLVL
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MET804
3.177
SER806
3.794
LYS808
4.869
PRO810
3.337
TRP812
4.578
ILE831
3.563
LYS833
3.708
ASP836
4.138
LEU838
3.660
ASP841
3.585
TYR867
3.774
ILE879
3.578
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Inositol phosphate metabolism | hsa00562 | Affiliated Target |
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| Class: Metabolism => Carbohydrate metabolism | Pathway Hierarchy | ||
| cGMP-PKG signaling pathway | hsa04022 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Chemokine signaling pathway | hsa04062 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Phospholipase D signaling pathway | hsa04072 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| PI3K-Akt signaling pathway | hsa04151 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Adrenergic signaling in cardiomyocytes | hsa04261 | Affiliated Target |
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| Class: Organismal Systems => Circulatory system | Pathway Hierarchy | ||
| Apelin signaling pathway | hsa04371 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Platelet activation | hsa04611 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Cholinergic synapse | hsa04725 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Oxytocin signaling pathway | hsa04921 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 19 | Degree centrality | 2.04E-03 | Betweenness centrality | 1.90E-03 |
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| Closeness centrality | 2.39E-01 | Radiality | 1.42E+01 | Clustering coefficient | 1.11E-01 |
| Neighborhood connectivity | 4.09E+01 | Topological coefficient | 8.64E-02 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| References | Top | |||||
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| REF 1 | ClinicalTrials.gov (NCT04372602) Duvelisib to Combat COVID-19. U.S. National Institutes of Health. | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 211155 | |||||
| REF 3 | Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946). ChemMedChem. 2016 Jul 19;11(14):1517-30. | |||||
| REF 4 | Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012 Feb;11(2):317-28. | |||||
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