protein kinase C theta | Delta subfamily | IUPHAR Guide to IMMUNOPHARMACOLOGY

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protein kinase C theta

  Target has curated data in GtoImmuPdb

Target id: 1488

Nomenclature: protein kinase C theta

Abbreviated Name: PKCθ

Family: Delta subfamily

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

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 706 10p15 PRKCQ protein kinase C theta
Mouse - 707 2 Prkcq protein kinase C, theta
Rat - 707 17q12.3 Prkcq protein kinase C, theta
Previous and Unofficial Names
PKC theta | PKC-theta | PRKCT | protein kinase C
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of PKC-theta complexed with Staurosporine at 2A resolution
PDB Id:  1XJD
Resolution:  2.0Å
Species:  Human
References:  13
Enzyme Reaction
EC Number: 2.7.11.13

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 Value Parameter Reference
PKCθ inhibitor 14 Hs Inhibition 9.6 pIC50 8
pIC50 9.6 (IC50 2.5x10-10 M) [8]
Description: In a biochemical assay.
sotrastaurin Hs Inhibition 9.0 pIC50 11
pIC50 9.0 (IC50 1x10-9 M) [11]
GSK690693 Hs Inhibition 8.7 pIC50 7
pIC50 8.7 (IC50 2x10-9 M) [7]
compound 41 [PMID: 25000588] Hs Inhibition 7.6 pIC50 6
pIC50 7.6 (IC50 2.3x10-8 M) [6]
Description: In a biochemical enzyme activity assay
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: 4,12

Key to terms and symbols Click column headers to sort
Target used in screen: PRKCQ
Ligand Sp. Type Action Value Parameter
ruboxistaurin Hs Inhibitor Inhibition 8.6 pKd
staurosporine Hs Inhibitor Inhibition 8.1 pKd
A-674563 Hs Inhibitor Inhibition 7.9 pKd
GSK690693 Hs Inhibitor Inhibition 7.8 pKd
enzastaurin Hs Inhibitor Inhibition 7.4 pKd
lestaurtinib Hs Inhibitor Inhibition 7.0 pKd
alvocidib Hs Inhibitor Inhibition 6.5 pKd
bosutinib Hs Inhibitor Inhibition 6.0 pKd
midostaurin Hs Inhibitor Inhibition 6.0 pKd
NVP-TAE684 Hs Inhibitor Inhibition 5.8 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 1,5

Key to terms and symbols Click column headers to sort
Target used in screen: PKCθ/PKCtheta
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 2.8 1.0 0.5
Gö 6983 Hs Inhibitor Inhibition 4.5 3.0 1.0
Ro-32-0432 Hs Inhibitor Inhibition 12.7
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 15.1 10.0 2.0
GF109203X Hs Inhibitor Inhibition 17.3 3.0 1.0
K-252a Hs Inhibitor Inhibition 22.5 10.0 5.0
bisindolylmaleimide IV Hs Inhibitor Inhibition 33.8 5.0 2.0
PKCbeta inhibitor Hs Inhibitor Inhibition 37.2 3.0 2.0
SB 218078 Hs Inhibitor Inhibition 43.2 7.0 13.0
sunitinib Hs Inhibitor Inhibition 63.5
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
PKC-θ is a novel subfamily PKC found predominantly in hematopoietic cells [2], and is the only PKC isoform selectively recruited to the immunological synapse in conventional effector T (Teff) cells. PKC-θ mediates early antigen recognition signal transduction and cell activation associated with T-cell receptor (TCR) stimulation [10]. PKCθ also plays an important role in generating the cell-suppressive function of Treg cells, where the immunological synapse formed is more stable than that formed in Teff cells [14].

Therapeutic potential for targeting PKC-θ as an anti-inflammatory modality: In light of the link between Treg cell insufficiency in autoimmune disease in human and animal models, and the role of PKCθ in regulating the balance between Teff and Treg cells, this enzyme has been targeted in drug discovery programmes [3,8-9]. For example, CC-90005 (Celgene), a selective PKCθ inhibitor with in vivo activity in the collagen-induced arthritis mouse model, progressed to Phase I clinical trial for psoriasis, but the trial was terminated (see NCT02502188). Potential for PKCθ inhibition in allogeneic transplantation, where inhibition of Teff cell responses would be of clinical benefit is reviewed in [9].
Immuno Process Associations
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes
GO:0045652 regulation of megakaryocyte differentiation TAS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 5 GO processes
GO:0050870 positive regulation of T cell activation ISS
GO:0070233 negative regulation of T cell apoptotic process IMP
GO:2000318 positive regulation of T-helper 17 type immune response ISS
GO:2000570 positive regulation of T-helper 2 cell activation ISS
click arrow to show/hide IEA associations
GO:0042102 positive regulation of T cell proliferation IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:2000318 positive regulation of T-helper 17 type immune response ISS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 7 GO processes
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0045652 regulation of megakaryocyte differentiation TAS
GO:0050852 T cell receptor signaling pathway TAS
GO:0050870 positive regulation of T cell activation ISS
GO:2000318 positive regulation of T-helper 17 type immune response ISS
GO:2000570 positive regulation of T-helper 2 cell activation ISS
click arrow to show/hide IEA associations
GO:0042102 positive regulation of T cell proliferation IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 3 GO processes
GO:0032740 positive regulation of interleukin-17 production ISS
GO:0032753 positive regulation of interleukin-4 production ISS
click arrow to show/hide IEA associations
GO:0045086 positive regulation of interleukin-2 biosynthetic process IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 3 GO processes
GO:0050870 positive regulation of T cell activation ISS
GO:2000570 positive regulation of T-helper 2 cell activation ISS
click arrow to show/hide IEA associations
GO:0042102 positive regulation of T cell proliferation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 5 GO processes
GO:0038095 Fc-epsilon receptor signaling pathway TAS
GO:0050852 T cell receptor signaling pathway TAS
GO:0050870 positive regulation of T cell activation ISS
GO:2000570 positive regulation of T-helper 2 cell activation ISS
click arrow to show/hide IEA associations
GO:0042102 positive regulation of T cell proliferation IEA
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0006954 inflammatory response IEA

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Baier G, Telford D, Giampa L, Coggeshall KM, Baier-Bitterlich G, Isakov N, Altman A. (1993) Molecular cloning and characterization of PKC theta, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells. J. Biol. Chem., 268 (7): 4997-5004. [PMID:8444877]

3. Chand S, Mehta N, Bahia MS, Dixit A, Silakari O. (2012) Protein kinase C-theta inhibitors: a novel therapy for inflammatory disorders. Curr. Pharm. Des., 18 (30): 4725-46. [PMID:22830352]

4. 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]

5. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

6. George DM, Breinlinger EC, Friedman M, Zhang Y, Wang J, Argiriadi M, Bansal-Pakala P, Barth M, Duignan DB, Honore P et al.. (2015) Discovery of selective and orally bioavailable protein kinase Cθ (PKCθ) inhibitors from a fragment hit. J. Med. Chem., 58 (1): 222-36. [PMID:25000588]

7. Heerding DA, Rhodes N, Leber JD, Clark TJ, Keenan RM, Lafrance LV, Li M, Safonov IG, Takata DT, Venslavsky JW et al.. (2008) Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. J. Med. Chem., 51 (18): 5663-79. [PMID:18800763]

8. Katoh T, Takai T, Yukawa T, Tsukamoto T, Watanabe E, Mototani H, Arita T, Hayashi H, Nakagawa H, Klein MG et al.. (2016) Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones as potent and selective PKCθ inhibitors. Bioorg. Med. Chem., 24 (11): 2466-75. [PMID:27117263]

9. Kwon MJ, Wang R, Ma J, Sun Z. (2010) PKC-θ is a drug target for prevention of T cell-mediated autoimmunity and allograft rejection. Endocr Metab Immune Disord Drug Targets, 10 (4): 367-72. [PMID:20923402]

10. Monks CR, Kupfer H, Tamir I, Barlow A, Kupfer A. (1997) Selective modulation of protein kinase C-theta during T-cell activation. Nature, 385 (6611): 83-6. [PMID:8985252]

11. Wagner J, von Matt P, Sedrani R, Albert R, Cooke N, Ehrhardt C, Geiser M, Rummel G, Stark W, Strauss A et al.. (2009) Discovery of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione (AEB071), a potent and selective inhibitor of protein kinase C isotypes. J. Med. Chem., 52 (20): 6193-6. [PMID:19827831]

12. 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]

13. Xu ZB, Chaudhary D, Olland S, Wolfrom S, Czerwinski R, Malakian K, Lin L, Stahl ML, Joseph-McCarthy D, Benander C et al.. (2004) Catalytic domain crystal structure of protein kinase C-theta (PKCtheta). J. Biol. Chem., 279 (48): 50401-9. [PMID:15364937]

14. Zanin-Zhorov A, Dustin ML, Blazar BR. (2011) PKC-θ function at the immunological synapse: prospects for therapeutic targeting. Trends Immunol., 32 (8): 358-63. [PMID:21733754]

How to cite this page

Delta subfamily: protein kinase C theta. Last modified on 17/02/2017. Accessed on 21/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1488.