Target General Infomation
Target ID
T67849
Former ID
TTDR00930
Target Name
PI3K delta
Gene Name
PIK3CD
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
Target Type
Successful
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.
BioChemical Class
Kinase
Target Validation
T67849
UniProt ID
EC Number
EC 2.7.1.153
Sequence
MPPGVDCPMEFWTKEENQSVVVDFLLPTGVYLNFPVSRNANLSTIKQLLWHRAQYEPLFH
MLSGPEAYVFTCINQTAEQQELEDEQRRLCDVQPFLPVLRLVAREGDRVKKLINSQISLL
IGKGLHEFDSLCDPEVNDFRAKMCQFCEEAAARRQQLGWEAWLQYSFPLQLEPSAQTWGP
GTLRLPNRALLVNVKFEGSEESFTFQVSTKDVPLALMACALRKKATVFRQPLVEQPEDYT
LQVNGRHEYLYGSYPLCQFQYICSCLHSGLTPHLTMVHSSSILAMRDEQSNPAPQVQKPR
AKPPPIPAKKPSSVSLWSLEQPFRIELIQGSKVNADERMKLVVQAGLFHGNEMLCKTVSS
SEVSVCSEPVWKQRLEFDINICDLPRMARLCFALYAVIEKAKKARSTKKKSKKADCPIAW
ANLMLFDYKDQLKTGERCLYMWPSVPDEKGELLNPTGTVRSNPNTDSAAALLICLPEVAP
HPVYYPALEKILELGRHSECVHVTEEEQLQLREILERRGSGELYEHEKDLVWKLRHEVQE
HFPEALARLLLVTKWNKHEDVAQMLYLLCSWPELPVLSALELLDFSFPDCHVGSFAIKSL
RKLTDDELFQYLLQLVQVLKYESYLDCELTKFLLDRALANRKIGHFLFWHLRSEMHVPSV
ALRFGLILEAYCRGSTHHMKVLMKQGEALSKLKALNDFVKLSSQKTPKPQTKELMHLCMR
QEAYLEALSHLQSPLDPSTLLAEVCVEQCTFMDSKMKPLWIMYSNEEAGSGGSVGIIFKN
GDDLRQDMLTLQMIQLMDVLWKQEGLDLRMTPYGCLPTGDRTGLIEVVLRSDTIANIQLN
KSNMAATAAFNKDALLNWLKSKNPGEALDRAIEEFTLSCAGYCVATYVLGIGDRHSDNIM
IRESGQLFHIDFGHFLGNFKTKFGINRERVPFILTYDFVHVIQQGKTNNSEKFERFRGYC
ERAYTILRRHGLLFLHLFALMRAAGLPELSCSKDIQYLKDSLALGKTEEEALKHFRVKFN
EALRESWKTKVNWLAHNVSKDNRQ
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 523366ClinicalTrials.gov (NCT01300026) AMG 319 Lymphoid Malignancy FIH. U.S. National Institutes of Health.
Ref 523929ClinicalTrials.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 524946ClinicalTrials.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 525260ClinicalTrials.gov (NCT02493530) TGR-1202 + Ruxolitinib PMF PPV-MF PET-MF MDS/MPN Polycythemia Vera Resistant to Hydroxyurea.
Ref 531469The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81.
Ref 532543PI3K-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 5331232014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
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 546241Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007058)
Ref 549071Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031939)
Ref 549495Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800038471)
Ref 550815Clinical pipeline report, company report or official report of Gilead.
Ref 526022Bioorg Med Chem Lett. 2001 Apr 9;11(7):909-13.LY294002-geldanamycin heterodimers as selective inhibitors of the PI3K and PI3K-related family.
Ref 531469The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81.
Ref 531635Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res. 2012 Jan;40(Database issue):D1128-36.
Ref 532543PI3K-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 5331232014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
Ref 535779Selective role of PI3K delta in neutrophil inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308(4):764-9.
Ref 537458The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009 Jun;9(5):550-9.
Ref 537633Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
Ref 549771INCB40093 is a selective PI3Kdelta inhibitor with potent antiproliferative activity against human B-cell tumors.
Ref 550469National Cancer Institute Drug Dictionary (drug id 696292).
Ref 550493National Cancer Institute Drug Dictionary (drug id 741949).
Ref 550639Clinical pipeline report, company report or official report of Exelixis.
Ref 550822Clinical pipeline report, company report or official report of Gilead.
Ref 551725Clinical pipeline report, company report or official report of TG Therapeutics.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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