phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta

Target id: 2155

Nomenclature: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta

Abbreviated Name: PI3Kδ

Family: Phosphatidylinositol-4,5-bisphosphate 3-kinase family, Phosphatidylinositol kinases

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

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Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1044 1p36.2 PIK3CD phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta 47
Mouse - 1047 4 E2 Pik3cd phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta
Rat - 944 5q36 Pik3cd phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta
Previous and Unofficial Names
PI3Kdelta | p110δ/PIK3CD | phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta | phosphatidylinositol-4 | phosphatidylinositol 3-kinase catalytic delta polypeptide
Database Links
BRENDA 2.7.1.153
CATH/Gene3D 1.10.1070.11, 2.60.40.150
Ensembl Gene ENSG00000171608 (Hs), ENSMUSG00000039936 (Mm), ENSRNOG00000016846 (Rn)
Entrez Gene 5293 (Hs), 18707 (Mm), 366508 (Rn)
GenitoUrinary Development Molecular Anatomy Project Pik3cd (Mm)
Human Protein Atlas ENSG00000171608 (Hs)
KEGG Enzyme 2.7.1.153
KEGG Gene hsa:5293 (Hs), mmu:18707 (Mm), rno:366508 (Rn)
OMIM 602839 (Hs)
RefSeq Nucleotide NM_005026 (Hs), NM_001029837 (Mm), NM_001108978 (Rn)
RefSeq Protein NP_005017 (Hs), NP_001025008 (Mm), NP_001102448 (Rn)
UniProtKB O00329 (Hs), O35904 (Mm)
Wikipedia PIK3CD (Hs)
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3KBeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers
PDB Id:  4AJW
Resolution:  2.8Å
Species:  Mouse
References:  12
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of the murine class IA PI 3-kinase p110delta in complex with IC-87114.
PDB Id:  2X38
Ligand:  IC-87114
Resolution:  2.2Å
Species:  Mouse
References:  7
Enzyme Reaction
EC Number: 2.7.1.153

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
IPI549 Hs Inhibition 7.6 pKd 19
pKd 7.6 (Kd 2.3x10-8 M) [19]
bimiralisib Hs Inhibition 7.6 pKd
pKd 7.6 (Kd 2.5x10-8 M)
LY 294002 Hs Inhibition 6.2 pKd 17
pKd 6.2 (Kd 7.1x10-7 M) [17]
taselisib Hs Inhibition 9.7 – 10.1 pKi 8,37
pKi 10.1 (Ki 7.9x10-11 M) [8]
pKi 9.7 (Ki 2.1x10-10 M) [37]
compound 82 [PMID: 21332118] Hs Inhibition 8.9 pKi 15
pKi 8.9 (Ki 1.2x10-9 M) [15]
pictilisib Hs Inhibition 8.8 pKi 8
pKi 8.8 (Ki 1.54x10-9 M) [8]
GDC-0077 Hs Inhibition 7.9 pKi 8
pKi 7.9 (Ki 1.22x10-8 M) [8]
IC-87114 Hs Inhibition ~7.7 pKi 30
pKi ~7.7 (Ki ~2x10-8 M) [30]
omipalisib Hs Inhibition 7.2 pKi 28
pKi 7.2 (Ki 6x10-8 M) [28]
KU-0060648 Hs Inhibition >10.0 pIC50 10
pIC50 >10.0 (IC50 <1x10-10 M) [10]
nemiralisib Hs Inhibition 9.9 pIC50 18
pIC50 9.9 (IC50 1.26x10-10 M) [18]
Description: In a homogeneous time-resolved fluorescence (HTRF) assay in the presence of 2mM ATP.
idelalisib Hs Inhibition 8.6 pIC50 31
pIC50 8.6 (IC50 2.5x10-9 M) in vitro activity against recombinant enzyme [31]
duvelisib Hs Inhibition 8.6 pIC50 48
pIC50 8.6 (IC50 2.5x10-9 M) [48]
pictilisib Hs Inhibition 8.5 pIC50 20
pIC50 8.5 (IC50 3x10-9 M) [20]
PI-103 Hs Inhibition 8.5 pIC50 42
pIC50 8.5 (IC50 3x10-9 M) [42]
ZSTK474 Hs Inhibition 8.2 – 8.3 pIC50 50-51
pIC50 8.2 – 8.3 (IC50 6x10-9 – 5x10-9 M) [50-51]
torin 2 Hs Inhibition 8.3 pIC50 34
pIC50 8.3 (IC50 5.67x10-9 M) [34]
AZD8835 Hs Inhibition 8.2 pIC50 6
pIC50 8.2 (IC50 5.7x10-9 M) [6]
apitolisib Hs Inhibition 8.2 pIC50 45
pIC50 8.2 (IC50 6.7x10-9 M) [45]
dactolisib Hs Inhibition 8.1 pIC50 36
pIC50 8.1 (IC50 7x10-9 M) [36]
AZD8186 Hs Inhibition 7.9 pIC50 23
pIC50 7.9 (IC50 1.2x10-8 M) [23]
seletalisib Hs Inhibition 7.9 pIC50 3
pIC50 7.9 (IC50 1.2x10-8 M) [3]
RP5264 Hs Inhibition 7.9 pIC50 46
pIC50 7.9 (IC50 1.383x10-8 M) [46]
PI-3065 Hs Inhibition 7.8 pIC50 2
pIC50 7.8 (IC50 1.5x10-8 M) [2]
AMG319 Hs Inhibition 7.7 pIC50 14
pIC50 7.7 (IC50 1.8x10-8 M) [14]
leniolisib Hs Inhibition 7.6 pIC50 13
pIC50 7.6 (IC50 2.3x10-8 M) [13]
Description: In vitro enzyme assay
pilaralisib Hs Inhibition 7.4 pIC50 50
pIC50 7.4 (IC50 3.6x10-8 M) [50]
LY3023414 Hs Inhibition 7.4 pIC50 5
pIC50 7.4 (IC50 3.8x10-8 M) [5]
CUDC-907 Hs Inhibition 7.4 pIC50 41
pIC50 7.4 (IC50 3.9x10-8 M) [41]
VS-5584 Hs Inhibition 7.4 pIC50 25
pIC50 7.4 (IC50 4.2x10-8 M) [25]
dezapelisib Hs Inhibition >7.3 pIC50 32
pIC50 >7.3 (IC50 <5x10-8 M) [32]
Description: The same value was obtained using an enzyme activity assay and a scintillation proximity assay.
AZD6482 Hs Inhibition 7.1 pIC50 38
pIC50 7.1 (IC50 8x10-8 M) [38]
TGX-221 Hs Inhibition 7.0 pIC50 27
pIC50 7.0 (IC50 1x10-7 M) [27]
PP121 Hs Inhibition 6.8 pIC50 4
pIC50 6.8 (IC50 1.5x10-7 M) [4]
LY 294002 Hs Inhibition 6.7 pIC50 10
pIC50 6.7 (IC50 2.2x10-7 M) [10]
INK-128 Hs Inhibition 6.6 pIC50 26
pIC50 6.6 (IC50 2.3x10-7 M) [26]
TG-100-115 Hs Inhibition 6.6 pIC50 40
pIC50 6.6 (IC50 2.35x10-7 M) [40]
alpelisib Hs Inhibition 6.5 pIC50 22
pIC50 6.5 (IC50 2.9x10-7 M) [22]
PI 3-Kg inhibitor Hs Inhibition 6.5 pIC50 9
pIC50 6.5 (IC50 3x10-7 M) [9]
compound 28 [PMID: 24387221] Hs Inhibition 6.3 pIC50 11
pIC50 6.3 (IC50 4.68x10-7 M) [11]
CH5132799 Hs Inhibition 6.3 pIC50 39
pIC50 6.3 (IC50 5x10-7 M) [39]
IC-87114 Hs Inhibition 6.3 pIC50 44
pIC50 6.3 (IC50 5x10-7 M) [44]
PIK-75 Hs Inhibition 6.3 pIC50 29
pIC50 6.3 (IC50 5.1x10-7 M) [29]
STK16-IN-1 Hs Inhibition 6.1 pIC50 33
pIC50 6.1 (IC50 8.56x10-7 M) [33]
Description: In an in vitro enzymatic assay.
eCF309 Hs Inhibition 5.7 pIC50 21
pIC50 5.7 (IC50 1.84x10-6 M) [21]
Description: In a biochemical assay.
serabelisib Hs Inhibition >5.0 pIC50 43
pIC50 >5.0 (IC50 <1x10-5 M) [43]
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
PIK-108 Hs Negative 6.2 pIC50 12
pIC50 6.2 (IC50 6.58x10-7 M) [12]
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 16,49
Key to terms and symbols Click column headers to sort
Target used in screen: PIK3CD
Ligand Sp. Type Action Affinity Units
pictilisib Hs Inhibitor Inhibition 8.3 pKd
PI-103 Hs Inhibitor Inhibition 7.8 pKd
PP-242 Hs Inhibitor Inhibition 7.5 pKd
TG-100-115 Hs Inhibitor Inhibition 6.6 pKd
ruboxistaurin Hs Inhibitor Inhibition <5.5 pKd
SB203580 Hs Inhibitor Inhibition <5.5 pKd
erlotinib Hs Inhibitor Inhibition <5.5 pKd
GSK690693 Hs Inhibitor Inhibition <5.5 pKd
masitinib Hs Inhibitor Inhibition <5.5 pKd
A-674563 Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
PI3Kδ is preferentially expressed in cells of hemopoietic lineage and is involved in neutrophil chemotaxis. It is the only PI3K isoform with expression restricted to leukocytes. Genetic and pharmacological inactivation of PI3Kδ indicates its importantance for the function of T cells, B cell, mast cells and neutrophils. PI3kδ is a promising target for drugs for preventing or treating inflammation, autoimmunity and transplant rejection [24], with selective PI3Kδ inhibitors of particular relevance- see for example AMG319 [14], leniolisib [13] and seletalisib [3].
The potential for PI3kδ as target in immuno-oncology is discussed in [1].
Cell Type Associations
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
References:  47
Immuno Cell Type:  T cells
Cell Ontology Term:   alpha-beta T cell (CL:0000789)
References:  47
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 9 GO processes
GO:0002551 mast cell chemotaxis TAS
GO:0006954 inflammatory response TAS
GO:0010818 T cell chemotaxis TAS
GO:0030593 neutrophil chemotaxis TAS
GO:0035747 natural killer cell chemotaxis TAS
GO:0035754 B cell chemotaxis TAS
GO:0043303 mast cell degranulation TAS
GO:0045087 innate immune response TAS
GO:0072672 neutrophil extravasation TAS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 3 GO processes
GO:0002250 adaptive immune response TAS
GO:0030217 T cell differentiation TAS
GO:0042110 T cell activation TAS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0002250 adaptive immune response TAS
GO:0042113 B cell activation TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 3 GO processes
GO:0033031 positive regulation of neutrophil apoptotic process IMP
GO:0050852 T cell receptor signaling pathway TAS
GO:0050853 B cell receptor signaling pathway TAS
Immuno Process:  Immune system development
GO Annotations:  Associated to 3 GO processes
GO:0001779 natural killer cell differentiation TAS
GO:0030217 T cell differentiation TAS
GO:0060374 mast cell differentiation TAS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 2 GO processes
GO:0001816 cytokine production TAS
GO:0038111 interleukin-7-mediated signaling pathway TAS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 6 GO processes
GO:0002551 mast cell chemotaxis TAS
GO:0010818 T cell chemotaxis TAS
GO:0030593 neutrophil chemotaxis TAS
GO:0035747 natural killer cell chemotaxis TAS
GO:0035754 B cell chemotaxis TAS
GO:0072672 neutrophil extravasation TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 8 GO processes
GO:0001779 natural killer cell differentiation TAS
GO:0030101 natural killer cell activation TAS
GO:0030217 T cell differentiation TAS
GO:0042110 T cell activation TAS
GO:0042113 B cell activation TAS
GO:0043303 mast cell degranulation TAS
GO:0050852 T cell receptor signaling pathway TAS
GO:0050853 B cell receptor signaling pathway TAS
Tissue Distribution
Leukocytes
Species:  Human
Technique:  Northern blot
References:  47
Lymphoid and myeloid cell populations, T cells, B cells (N.B. platelets negative)
Species:  Human
Technique:  Immunocytochemistry
References:  47
Spleen and thymus
Species:  Rat
Technique:  Immunohistochemistry
References:  47
Clinically-Relevant Mutations and Pathophysiology
Disease:  Activated PI3K delta syndrome
Description: A rare autosomal dominant, genetic disease causing primary immunodeficiency and characterised by lymphadenopathy, immunodeficiency leading to recurrent infections, and an increased risk of EBV-associated lymphoma.
Synonyms: APDS/PASLI
Immunodeficiency 14
p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency
OMIM: 615513
Orphanet: ORPHA397596
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense, gain of function Human N334K; E525K; E1021K 1002 C>A; 1573 G>A; 3061 G>A N334K is in the C2 domain, E525K is in the helical domain and E1021K is in the C-lobe of the kinase domain. 35
General Comments
PI3Kδ belongs to the class IA phospho-inositide-3-kinases (PI3Ks). In common with PI3Kα and PI3Kβ, PI3Kδ displays a broad phosphoinositide lipid substrate specificity. It interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras. Expression of PI3Kδ is restricted to leukocytes [47], whereas PI3Kα and PI3Kβ are widely expressed.

References

Show »

1. Adams JL, Smothers J, Srinivasan R, Hoos A. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov, 14 (9): 603-22. [PMID:26228631]

2. Ali K, Soond DR, Piñeiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H et al.. (2014) Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature, 510 (7505): 407-11. [PMID:24919154]

3. Allen RA, Brookings DC, Powell MJ, Delgado J, Shuttleworth LK, Merriman M, Fahy IJ, Tewari R, Silva JP, Healy LJ et al.. (2017) Seletalisib: Characterization of a Novel, Potent, and Selective Inhibitor of PI3Kδ. J. Pharmacol. Exp. Ther., 361 (3): 429-440. [PMID:28442583]

4. Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM, Knight ZA. (2008) Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat. Chem. Biol., 4 (11): 691-9. [PMID:18849971]

5. Barda DA, Mader MM. (2013) PI3 kinase/mTOR dual inhibitor. Patent number: US8440829 B2. Assignee: Eli Lilly And Company. Priority date: 14/01/2011. Publication date: 14/05/2013.

6. Barlaam B, Cosulich S, Delouvrié B, Ellston R, Fitzek M, Germain H, Green S, Hancox U, Harris CS, Hudson K et al.. (2015) Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of cancers. Bioorg. Med. Chem. Lett., 25 (22): 5155-62. [PMID:26475521]

7. Berndt A, Miller S, Williams O, Le DD, Houseman BT, Pacold JI, Gorrec F, Hon WC, Liu Y, Rommel C et al.. (2010) The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat. Chem. Biol., 6 (2): 117-24. [PMID:20081827]

8. Braun M-G, Hanan E, Staben ST, Heald RA, Macleod C, Elliott R. (2017) Benzoxazepin oxazolidinone compounds and methods of use. Patent number: US20170015678. Assignee: Genentech, Inc.. Priority date: 02/07/2015. Publication date: 19/01/2017.

9. Camps M, Rückle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Françon B et al.. (2005) Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat. Med., 11 (9): 936-43. [PMID:16127437]

10. Cano C, Saravanan K, Bailey C, Bardos J, Curtin NJ, Frigerio M, Golding BT, Hardcastle IR, Hummersone MG, Menear KA et al.. (2013) 1-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity. J. Med. Chem., 56 (16): 6386-401. [PMID:23855836]

11. Certal V, Carry JC, Halley F, Virone-Oddos A, Thompson F, Filoche-Rommé B, El-Ahmad Y, Karlsson A, Charrier V, Delorme C et al.. (2014) Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers. J. Med. Chem., 57 (3): 903-20. [PMID:24387221]

12. Certal V, Halley F, Virone-Oddos A, Delorme C, Karlsson A, Rak A, Thompson F, Filoche-Rommé B, El-Ahmad Y, Carry JC et al.. (2012) Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. J. Med. Chem., 55 (10): 4788-805. [PMID:22524426]

13. Cooke NG, Fernandes GDSP, Graveleau N, Hebach C, Hogenauer K, Hollingworth G, Smith AB, Soldermann N, Stowasser F, Strang R et al.. (2012) Tetrahydro-pyrido-pyrimidine derivatives. Patent number: WO2012004299. Assignee: Novartis Ag. Priority date: 06/07/2010. Publication date: 12/01/2012.

14. Cushing TD, Hao X, Shin Y, Andrews K, Brown M, Cardozo M, Chen Y, Duquette J, Fisher B, Gonzalez-Lopez de Turiso F et al.. (2015) Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease. J. Med. Chem., 58 (1): 480-511. [PMID:25469863]

15. D'Angelo ND, Kim TS, Andrews K, Booker SK, Caenepeel S, Chen K, D'Amico D, Freeman D, Jiang J, Liu L et al.. (2011) Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors. J. Med. Chem., 54 (6): 1789-811. [PMID:21332118]

16. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

17. Dittmann A, Werner T, Chung CW, Savitski MM, Fälth Savitski M, Grandi P, Hopf C, Lindon M, Neubauer G, Prinjha RK et al.. (2014) The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains. ACS Chem. Biol., 9 (2): 495-502. [PMID:24533473]

18. Down K, Amour A, Baldwin IR, Cooper AW, Deakin AM, Felton LM, Guntrip SB, Hardy C, Harrison ZA, Jones KL et al.. (2015) Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease. J. Med. Chem., 58 (18): 7381-99. [PMID:26301626]

19. Evans CA, Liu T, Lescarbeau A, Nair SJ, Grenier L, Pradeilles JA, Glenadel Q, Tibbitts T, Rowley AM, DiNitto JP et al.. (2016) Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate. ACS Med Chem Lett, 7 (9): 862-7. [PMID:27660692]

20. Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA et al.. (2008) 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., 51 (18): 5522-32. [PMID:18754654]

21. Fraser C, Carragher NO, Unciti-Broceta A. (2016) eCF309: a potent, selective and cell-permeable mTOR inhibitor. Med. Chem. Commun., 7 (3): 471-477.

22. Furet P, Guagnano V, Fairhurst RA, Imbach-Weese P, Bruce I, Knapp M, Fritsch C, Blasco F, Blanz J, Aichholz R et al.. (2013) Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett., 23 (13): 3741-8. [PMID:23726034]

23. Hancox U, Cosulich S, Hanson L, Trigwell C, Lenaghan C, Ellston R, Dry H, Crafter C, Barlaam B, Fitzek M et al.. (2015) Inhibition of PI3Kβ signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel. Mol. Cancer Ther., 14 (1): 48-58. [PMID:25398829]

24. Harris SJ, Foster JG, Ward SG. (2009) PI3K isoforms as drug targets in inflammatory diseases: lessons from pharmacological and genetic strategies. Curr Opin Investig Drugs, 10 (11): 1151-62. [PMID:19876783]

25. Hart S, Novotny-Diermayr V, Goh KC, Williams M, Tan YC, Ong LC, Cheong A, Ng BK, Amalini C, Madan B et al.. (2013) VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer. Mol. Cancer Ther., 12 (2): 151-61. [PMID:23270925]

26. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, Shi EY, Stumpf CR, Christensen C, Bonham MJ et al.. (2012) The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature, 485 (7396): 55-61. [PMID:22367541]

27. Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y et al.. (2005) PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat. Med., 11 (5): 507-14. [PMID:15834429]

28. Knight SD, Adams ND, Burgess JL, Chaudhari AM, Darcy MG, Donatelli CA, Luengo JI, Newlander KA, Parrish CA, Ridgers LH et al.. (2010) Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Med Chem Lett, 1 (1): 39-43. [PMID:24900173]

29. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B et al.. (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell, 125 (4): 733-47. [PMID:16647110]

30. Knight ZA, Shokat KM. (2005) Features of selective kinase inhibitors. Chem. Biol., 12 (6): 621-37. [PMID:15975507]

31. Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, Byrd JC, Tyner JW, Loriaux MM, Deininger M et al.. (2011) CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood, 117 (2): 591-4. [PMID:20959606]

32. Li Y-L, Metcalf BW, Combs AP. (2011) Pyrimidinones as PI3K inhibitors. Patent number: WO2011008487. Assignee: Incyte Corporation. Priority date: 29/06/2009. Publication date: 20/01/2011.

33. Liu F, Wang J, Yang X, Li B, Wu H, Qi S, Chen C, Liu X, Yu K, Wang W et al.. (2016) Discovery of a Highly Selective STK16 Kinase Inhibitor. ACS Chem. Biol., 11 (6): 1537-43. [PMID:27082499]

34. Liu Q, Wang J, Kang SA, Thoreen CC, Hur W, Ahmed T, Sabatini DM, Gray NS. (2011) Discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one (Torin2) as a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer. J. Med. Chem., 54 (5): 1473-80. [PMID:21322566]

35. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M et al.. (2014) Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat. Immunol., 15 (1): 88-97. [PMID:24165795]

36. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, De Pover A, Schoemaker K et al.. (2008) Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther., 7 (7): 1851-63. [PMID:18606717]

37. Ndubaku CO, Heffron TP, Staben ST, Baumgardner M, Blaquiere N, Bradley E, Bull R, Do S, Dotson J, Dudley D et al.. (2013) Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J. Med. Chem., 56 (11): 4597-610. [PMID:23662903]

38. Nylander S, Kull B, Björkman JA, Ulvinge JC, Oakes N, Emanuelsson BM, Andersson M, Skärby T, Inghardt T, Fjellström O et al.. (2012) Human target validation of phosphoinositide 3-kinase (PI3K)β: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor. J. Thromb. Haemost., 10 (10): 2127-36. [PMID:22906130]

39. Ohwada J, Ebiike H, Kawada H, Tsukazaki M, Nakamura M, Miyazaki T, Morikami K, Yoshinari K, Yoshida M, Kondoh O et al.. (2011) Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799. Bioorg. Med. Chem. Lett., 21 (6): 1767-72. [PMID:21316229]

40. Palanki MS, Dneprovskaia E, Doukas J, Fine RM, Hood J, Kang X, Lohse D, Martin M, Noronha G, Soll RM et al.. (2007) Discovery of 3,3'-(2,4-diaminopteridine-6,7-diyl)diphenol as an isozyme-selective inhibitor of PI3K for the treatment of ischemia reperfusion injury associated with myocardial infarction. J. Med. Chem., 50 (18): 4279-94. [PMID:17685602]

41. Qian C, Lai CJ, Bao R, Wang DG, Wang J, Xu GX, Atoyan R, Qu H, Yin L, Samson M et al.. (2012) Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling. Clin. Cancer Res., 18 (15): 4104-13. [PMID:22693356]

42. Raynaud FI, Eccles SA, Patel S, Alix S, Box G, Chuckowree I, Folkes A, Gowan S, De Haven Brandon A, Di Stefano F et al.. (2009) Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol. Cancer Ther., 8 (7): 1725-38. [PMID:19584227]

43. Ren P, Liu Y, Li L, Chan K, Wilson TE, Campbell SF. (2013) Heterocyclic compounds and uses thereof. Patent number: US20130035324 A1. Assignee: Ren P, Liu Y, Li L, Chan K, Wilson TE, Campbell SF.. Priority date: 17/08/2009. Publication date: 07/02/2013.

44. Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE. (2003) Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement. J. Immunol., 170 (5): 2647-54. [PMID:12594293]

45. Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, Dotson J, Folks A, Friedman L, Goldsmith R, Gunzner J et al.. (2011) Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J. Med. Chem., 54 (21): 7579-87. [PMID:21981714]

46. Vakkalanka SKVS, Muthuppalaniappan M, Nagarathnam D. (2014) Novel selective pi3k delta inhibitors. Patent number: US20140011819 A1. Assignee: Rhizen Pharmaceuticals Sa.. Priority date: 04/07/2012. Publication date: 09/01/2014.

47. Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, Higashi K, Volinia S, Downward J, Waterfield MD. (1997) P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc. Natl. Acad. Sci. U.S.A., 94 (9): 4330-5. [PMID:9113989]

48. Winkler DG, Faia KL, DiNitto JP, Ali JA, White KF, Brophy EE, Pink MM, Proctor JL, Lussier J, Martin CM et al.. (2013) PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem. Biol., 20 (11): 1364-74. [PMID:24211136]

49. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

50. Wu P, Hu Y. (2012) Small molecules targeting phosphoinositide 3-kinases. Med. Chem. Commun., 3 (11): 1337-1355.

51. Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H, Hirono S, Yamazaki K, Yamori T. (2006) Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J. Natl. Cancer Inst., 98 (8): 545-56. [PMID:16622124]

How to cite this page

Phosphatidylinositol kinases: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta. Last modified on 08/02/2018. Accessed on 23/04/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2155.