Target Information
Target General Infomation | |||||
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Target ID |
T67849
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Former ID |
TTDR00930
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Target Name |
PI3K delta
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Gene Name |
PIK3CD
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Synonyms |
P110delta; PI3-kinase p110 subunit delta; PI3K; Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, delta isoform; Phosphoinositide 3-kinase delta; PtdIns-3-kinase p110; PIK3CD
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Target Type |
Successful
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Disease | Arthritis [ICD9: 710-719; ICD10: M00-M25] | ||||
Breast cancer [ICD9: 174, 175; ICD10: C50] | |||||
Chronic lymphocytic leukaemia [ICD10: C91] | |||||
Cancer [ICD9: 140-229; ICD10: C00-C96] | |||||
Chronic lymphocytic leukaemia; Lymphoma [ICD9:202.8, 208.9; ICD10: C91, C81-C86] | |||||
Hematologic malignancies; Myeloid leukemia [ICD9:200-209, 208.9; ICD10: C81-C86, C92] | |||||
Hematological malignancies [ICD9: 200-209; ICD10: C81-C86] | |||||
Hematologic malignancies [ICD9: 200-209; ICD10: C81-C86] | |||||
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86] | |||||
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48] | |||||
Function |
Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(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. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG isinvolved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity.
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BioChemical Class |
Kinase
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Target Validation |
T67849
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UniProt ID | |||||
EC Number |
EC 2.7.1.153
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Sequence |
MPPGVDCPMEFWTKEENQSVVVDFLLPTGVYLNFPVSRNANLSTIKQLLWHRAQYEPLFH
MLSGPEAYVFTCINQTAEQQELEDEQRRLCDVQPFLPVLRLVAREGDRVKKLINSQISLL IGKGLHEFDSLCDPEVNDFRAKMCQFCEEAAARRQQLGWEAWLQYSFPLQLEPSAQTWGP GTLRLPNRALLVNVKFEGSEESFTFQVSTKDVPLALMACALRKKATVFRQPLVEQPEDYT LQVNGRHEYLYGSYPLCQFQYICSCLHSGLTPHLTMVHSSSILAMRDEQSNPAPQVQKPR AKPPPIPAKKPSSVSLWSLEQPFRIELIQGSKVNADERMKLVVQAGLFHGNEMLCKTVSS SEVSVCSEPVWKQRLEFDINICDLPRMARLCFALYAVIEKAKKARSTKKKSKKADCPIAW ANLMLFDYKDQLKTGERCLYMWPSVPDEKGELLNPTGTVRSNPNTDSAAALLICLPEVAP HPVYYPALEKILELGRHSECVHVTEEEQLQLREILERRGSGELYEHEKDLVWKLRHEVQE HFPEALARLLLVTKWNKHEDVAQMLYLLCSWPELPVLSALELLDFSFPDCHVGSFAIKSL RKLTDDELFQYLLQLVQVLKYESYLDCELTKFLLDRALANRKIGHFLFWHLRSEMHVPSV ALRFGLILEAYCRGSTHHMKVLMKQGEALSKLKALNDFVKLSSQKTPKPQTKELMHLCMR QEAYLEALSHLQSPLDPSTLLAEVCVEQCTFMDSKMKPLWIMYSNEEAGSGGSVGIIFKN GDDLRQDMLTLQMIQLMDVLWKQEGLDLRMTPYGCLPTGDRTGLIEVVLRSDTIANIQLN KSNMAATAAFNKDALLNWLKSKNPGEALDRAIEEFTLSCAGYCVATYVLGIGDRHSDNIM IRESGQLFHIDFGHFLGNFKTKFGINRERVPFILTYDFVHVIQQGKTNNSEKFERFRGYC ERAYTILRRHGLLFLHLFALMRAAGLPELSCSKDIQYLKDSLALGKTEEEALKHFRVKFN EALRESWKTKVNWLAHNVSKDNRQ |
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Drugs and Mode of Action | |||||
Drug(s) | Idelalisib | Drug Info | Approved | Chronic lymphocytic leukaemia | [533123], [541841] |
Buparlisib | Drug Info | Phase 3 | Breast cancer | [523929], [542804] | |
IPI-145 | Drug Info | Phase 3 | Arthritis | [532543], [542746] | |
INCB40093 | Drug Info | Phase 1/2 | Lymphoma | [549495] | |
AMG 319 | Drug Info | Phase 1 | Hematologic malignancies; Myeloid leukemia | [523366] | |
CH-5132799 | Drug Info | Phase 1 | Solid tumours | [531469], [542708] | |
GS-9820 | Drug Info | Phase 1 | Chronic lymphocytic leukaemia; Lymphoma | [550815] | |
GS-9901 | Drug Info | Phase 1 | Hematological malignancies | [524946] | |
TGR-1202 | Drug Info | Phase 1 | Hematological malignancies | [525260] | |
XL-499 | Drug Info | Preclinical | Cancer | [549071] | |
Wortmannin | Drug Info | Terminated | Hematologic malignancies | [541309], [546241] | |
Inhibitor | AMG 319 | Drug Info | [550469] | ||
Buparlisib | Drug Info | [537633] | |||
CH-5132799 | Drug Info | [531469] | |||
GS-9820 | Drug Info | [550493] | |||
GS-9901 | Drug Info | [531635], [550822] | |||
IC87114 | Drug Info | [535779] | |||
IC980033 | Drug Info | [535779] | |||
Idelalisib | Drug Info | [533123] | |||
INCB40093 | Drug Info | [549771] | |||
LY-292223 | Drug Info | [526022] | |||
LY-293646 | Drug Info | [526022] | |||
TGR-1202 | Drug Info | [551725] | |||
Wortmannin | Drug Info | [535779], [537458] | |||
XL-499 | Drug Info | [550639] | |||
Modulator | IPI-145 | Drug Info | [532543] | ||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
BioCyc Pathway | Superpathway of inositol phosphate compounds | ||||
3-phosphoinositide biosynthesis | |||||
KEGG Pathway | Inositol phosphate metabolism | ||||
ErbB signaling pathway | |||||
Ras signaling pathway | |||||
Rap1 signaling pathway | |||||
cGMP-PKG signaling pathway | |||||
cAMP signaling pathway | |||||
Chemokine signaling pathway | |||||
HIF-1 signaling pathway | |||||
FoxO signaling pathway | |||||
Phosphatidylinositol signaling system | |||||
Sphingolipid signaling pathway | |||||
mTOR signaling pathway | |||||
PI3K-Akt signaling pathway | |||||
AMPK signaling pathway | |||||
Apoptosis | |||||
Adrenergic signaling in cardiomyocytes | |||||
VEGF signaling pathway | |||||
Osteoclast differentiation | |||||
Focal adhesion | |||||
Signaling pathways regulating pluripotency of stem cells | |||||
Platelet activation | |||||
Toll-like receptor signaling pathway | |||||
Jak-STAT signaling pathway | |||||
Natural killer cell mediated cytotoxicity | |||||
T cell receptor signaling pathway | |||||
B cell receptor signaling pathway | |||||
Fc epsilon RI signaling pathway | |||||
Fc gamma R-mediated phagocytosis | |||||
TNF signaling pathway | |||||
Leukocyte transendothelial migration | |||||
Neurotrophin signaling pathway | |||||
Cholinergic synapse | |||||
Inflammatory mediator regulation of TRP channels | |||||
Regulation of actin cytoskeleton | |||||
Insulin signaling pathway | |||||
Progesterone-mediated oocyte maturation | |||||
Estrogen signaling pathway | |||||
Prolactin signaling pathway | |||||
Thyroid hormone signaling pathway | |||||
Oxytocin signaling pathway | |||||
Regulation of lipolysis in adipocytes | |||||
Type II diabetes mellitus | |||||
Non-alcoholic fatty liver disease (NAFLD) | |||||
Aldosterone-regulated sodium reabsorption | |||||
Carbohydrate digestion and absorption | |||||
Bacterial invasion of epithelial cells | |||||
Chagas disease (American trypanosomiasis) | |||||
Toxoplasmosis | |||||
Amoebiasis | |||||
Hepatitis C | |||||
Hepatitis B | |||||
Measles | |||||
Influenza A | |||||
HTLV-I infection | |||||
Epstein-Barr virus infection | |||||
Pathways in cancer | |||||
Viral carcinogenesis | |||||
Proteoglycans in cancer | |||||
Colorectal cancer | |||||
Renal cell carcinoma | |||||
Pancreatic cancer | |||||
Endometrial cancer | |||||
Glioma | |||||
Prostate cancer | |||||
Melanoma | |||||
Chronic myeloid leukemia | |||||
Acute myeloid leukemia | |||||
Small cell lung cancer | |||||
Non-small cell lung cancer | |||||
Central carbon metabolism in cancer | |||||
Choline metabolism in cancer | |||||
NetPath Pathway | FSH Signaling Pathway | ||||
PANTHER Pathway | Angiogenesis | ||||
Apoptosis signaling pathway | |||||
Axon guidance mediated by netrin | |||||
B cell activation | |||||
EGF receptor signaling pathway | |||||
Endothelin signaling pathway | |||||
FGF signaling pathway | |||||
Hypoxia response via HIF activation | |||||
Inflammation mediated by chemokine and cytokine signaling pathway | |||||
Insulin/IGF pathway-protein kinase B signaling cascade | |||||
Integrin signalling pathway | |||||
PDGF signaling pathway | |||||
T cell activation | |||||
VEGF signaling pathway | |||||
p53 pathway | |||||
Ras Pathway | |||||
p53 pathway feedback loops 2 | |||||
Pathway Interaction Database | ErbB4 signaling events | ||||
TRAIL signaling pathway | |||||
Signaling events mediated by TCPTP | |||||
FAS (CD95) signaling pathway | |||||
CXCR4-mediated signaling events | |||||
EGF receptor (ErbB1) signaling pathway | |||||
Class I PI3K signaling events | |||||
ErbB1 downstream signaling | |||||
ErbB2/ErbB3 signaling events | |||||
PDGFR-beta signaling pathway | |||||
Nephrin/Neph1 signaling in the kidney podocyte | |||||
Internalization of ErbB1 | |||||
CXCR3-mediated signaling events | |||||
PathWhiz Pathway | Phosphatidylinositol Phosphate Metabolism | ||||
Reactome | GPVI-mediated activation cascade | ||||
PIP3 activates AKT signaling | |||||
Constitutive Signaling by Aberrant PI3K in Cancer | |||||
gamma signalling through PI3Kgamma | |||||
Interleukin-3, 5 and GM-CSF signaling | |||||
Interleukin receptor SHC signaling | |||||
Regulation of signaling by CBL | |||||
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers | |||||
WikiPathways | Toll-like receptor signaling pathway | ||||
DNA Damage Response (only ATM dependent) | |||||
Interferon type I signaling pathways | |||||
G13 Signaling Pathway | |||||
Regulation of Actin Cytoskeleton | |||||
Insulin Signaling | |||||
IL-4 Signaling Pathway | |||||
Focal Adhesion | |||||
IL-3 Signaling Pathway | |||||
PI Metabolism | |||||
Signaling by the B Cell Receptor (BCR) | |||||
Interleukin-2 signaling | |||||
PIP3 activates AKT signaling | |||||
Nanoparticle-mediated activation of receptor signaling | |||||
Signaling Pathways in Glioblastoma | |||||
Interleukin-3, 5 and GM-CSF signaling | |||||
MicroRNAs in cardiomyocyte hypertrophy | |||||
Regulation of toll-like receptor signaling pathway | |||||
AMPK Signaling | |||||
References | |||||
Ref 523366 | ClinicalTrials.gov (NCT01300026) AMG 319 Lymphoid Malignancy FIH. U.S. National Institutes of Health. | ||||
Ref 523929 | ClinicalTrials.gov (NCT01610284) Phase III Study of BKM120/Placebo With Fulvestrant in Postmenopausal Patients With Hormone Receptor Positive HER2-negative Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitor. U.S. National Institutes of Health. | ||||
Ref 524946 | ClinicalTrials.gov (NCT02258555) Safety, Pharmacodynamics, Pharmacokinetics, and Efficacy of GS-9901 in Adults With Relapsed or Refractory Follicular Lymphoma, Marginal Zone Lymphoma, Chronic Lymphocytic Leukemia, or Small Lymphocytic Lymphoma. U.S. National Institutes of Health. | ||||
Ref 525260 | ClinicalTrials.gov (NCT02493530) TGR-1202 + Ruxolitinib PMF PPV-MF PET-MF MDS/MPN Polycythemia Vera Resistant to Hydroxyurea. | ||||
Ref 531469 | The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81. | ||||
Ref 532543 | PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol. 2013 Nov 21;20(11):1364-74. | ||||
Ref 541309 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6060). | ||||
Ref 541841 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6741). | ||||
Ref 542708 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7743). | ||||
Ref 542746 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7795). | ||||
Ref 542804 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7878). | ||||
Ref 546241 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007058) | ||||
Ref 549071 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031939) | ||||
Ref 526022 | Bioorg Med Chem Lett. 2001 Apr 9;11(7):909-13.LY294002-geldanamycin heterodimers as selective inhibitors of the PI3K and PI3K-related family. | ||||
Ref 531469 | The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81. | ||||
Ref 531635 | Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res. 2012 Jan;40(Database issue):D1128-36. | ||||
Ref 532543 | PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol. 2013 Nov 21;20(11):1364-74. | ||||
Ref 535779 | Selective role of PI3K delta in neutrophil inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308(4):764-9. | ||||
Ref 537458 | The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009 Jun;9(5):550-9. | ||||
Ref 537633 | Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44. |
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