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protein kinase C theta

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 1488

Nomenclature: protein kinase C theta

Abbreviated Name: PKCθ

Family: Delta subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 706 10p15.1 PRKCQ protein kinase C theta
Mouse - 707 2 8.42 cM Prkcq protein kinase C, theta
Rat - 707 17q12.3 Prkcq protein kinase C, theta
Previous and Unofficial Names Click here for help
PKC theta | PKC-theta | PRKCT | protein kinase C
Database Links Click here for help
Alphafold Q04759 (Hs), Q02111 (Mm), Q9WTQ0 (Rn)
BRENDA 2.7.11.13
ChEMBL Target CHEMBL3920 (Hs), CHEMBL1075295 (Mm)
Ensembl Gene ENSG00000065675 (Hs), ENSMUSG00000026778 (Mm), ENSRNOG00000019057 (Rn)
Entrez Gene 5588 (Hs), 18761 (Mm), 85420 (Rn)
Human Protein Atlas ENSG00000065675 (Hs)
KEGG Enzyme 2.7.11.13
KEGG Gene hsa:5588 (Hs), mmu:18761 (Mm), rno:85420 (Rn)
OMIM 600448 (Hs)
Pharos Q04759 (Hs)
RefSeq Nucleotide NM_001242413 (Hs), NM_008859 (Mm), NM_001276721 (Rn)
RefSeq Protein NP_006248 (Hs), NP_032885 (Mm), NP_001263650 (Rn)
UniProtKB Q04759 (Hs), Q02111 (Mm), Q9WTQ0 (Rn)
Wikipedia PRKCQ (Hs)
Selected 3D Structures Click here for help
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:  19
Enzyme Reaction Click here for help
EC Number: 2.7.11.13

Download all structure-activity data for this target as a CSV file go icon to follow link

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
10-Me-Aplog-1 Small molecule or natural product Click here for species-specific activity table Hs Activation 9.3 pKi 10
⤷ pKi 9.3 (Ki 5.4x10-10 M) [10]
Description: Binding affinity for the C1B domain of PKCθ, determined by inhibition of [3H]PDBu binding
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PKCθ inhibitor 14 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 9.6 pIC50 9
⤷ pIC50 9.6 (IC50 2.5x10-10 M) [9]
Description: In a biochemical assay.
darovasertib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.4 pIC50 13
⤷ pIC50 9.4 (IC50 4x10-10 M) [13]
sotrastaurin Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 9.0 pIC50 17
⤷ pIC50 9.0 (IC50 1x10-9 M) [17]
GSK690693 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.7 pIC50 8
⤷ pIC50 8.7 (IC50 2x10-9 M) [8]
CC-90005 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 15
⤷ pIC50 8.1 (IC50 8x10-9 M) [15]
compound 41 [PMID: 25000588] Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 7.6 pIC50 7
⤷ pIC50 7.6 (IC50 2.3x10-8 M) [7]
Description: In a biochemical enzyme activity assay
aplithianine A Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pIC50 5
⤷ pIC50 7.4 (IC50 3.6x10-8 M) [5]
DiscoveRx KINOMEscan® screen Click here for help
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: 4,18
Key to terms and symbols Click column headers to sort
Target used in screen: PRKCQ
Ligand Sp. Type Action Value Parameter
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.6 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.1 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.9 pKd
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
enzastaurin Small molecule or natural product Hs Inhibitor Inhibition 7.4 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.0 pKd
alvocidib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.0 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.0 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure 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 Click here for help
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: 1,6
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.8 1.0 0.5
Gö 6983 Small molecule or natural product Hs Inhibitor Inhibition 4.5 3.0 1.0
Ro-32-0432 Small molecule or natural product Hs Inhibitor Inhibition 12.7
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 15.1 10.0 2.0
GF109203X Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 17.3 3.0 1.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 22.5 10.0 5.0
bisindolylmaleimide IV Small molecule or natural product Hs Inhibitor Inhibition 33.8 5.0 2.0
PKCbeta inhibitor Small molecule or natural product Hs Inhibitor Inhibition 37.2 3.0 2.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 43.2 7.0 13.0
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure 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 [14]. 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 [20].

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 [3,9,11]. 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 [11]. Darovasertib has some selectivity for PKC-θ, and it was advanced into clinical studies for oncology indications.
Cell Type Associations
Immuno Cell Type:  T cells
Comment:  PKDθ is expressed predominantly in T lymphocytes.
References:  2
Immuno Cell Type:  Mast cells
References:  12
Immuno Cell Type:  Natural killer cells
References:  16
Immuno Process Associations
Immuno Process:  Immune system development
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Immuno Process:  Inflammation
Immuno Process:  Tissue repair

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. Du L, Wilson BAP, Li N, Shah R, Dalilian M, Wang D, Smith EA, Wamiru A, Goncharova EI, Zhang P et al.. (2023) Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases. J Nat Prod, 86 (10): 2283-2293. [PMID:37843072]

6. 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]

7. 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]

8. 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]

9. 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]

10. Kikumori M, Yanagita RC, Tokuda H, Suzuki N, Nagai H, Suenaga K, Irie K. (2012) Structure-activity studies on the spiroketal moiety of a simplified analogue of debromoaplysiatoxin with antiproliferative activity. J Med Chem, 55 (11): 5614-26. [PMID:22625994]

11. 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]

12. Liu Y, Graham C, Parravicini V, Brown MJ, Rivera J, Shaw S. (2001) Protein kinase C theta is expressed in mast cells and is functionally involved in Fcepsilon receptor I signaling. J Leukoc Biol, 69 (5): 831-40. [PMID:11358993]

13. Luzzio MJ, Papillon J, Visser MS. (2016) Protein kinase C inhibitors and methods of their use. Patent number: WO2016020864A1. Assignee: Novartis Ag. Priority date: 06/08/2014. Publication date: 11/02/2016.

14. 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]

15. Papa P, Whitefield B, Mortensen DS, Cashion D, Huang D, Torres E, Parnes J, Sapienza J, Hansen J, Correa M et al.. (2021) Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005. J Med Chem, 64 (16): 11886-11903. [PMID:34355886]

16. Vyas YM, Mehta KM, Morgan M, Maniar H, Butros L, Jung S, Burkhardt JK, Dupont B. (2001) Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions. J Immunol, 167 (8): 4358-67. [PMID:11591760]

17. 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]

18. 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]

19. 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]

20. 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]

Contributors

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How to cite this page

Mohib Uddin.
Delta subfamily: protein kinase C theta. Last modified on 06/06/2024. Accessed on 10/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1488.