General Information of Drug Therapeutic Target (DTT) (ID: TT9WJ8U)

DTT Name Protein kinase C delta (PRKCD)
Synonyms nPKC-delta; Tyrosine-protein kinase PRKCD; SDK1; Protein kinase C delta type catalytic subunit; Protein kinase C delta type; PKC-delta
Gene Name PRKCD
DTT Type
Clinical trial target
[1]
BioChemical Class
Kinase
UniProt ID
KPCD_HUMAN
TTD ID
T44861
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
EC 2.7.11.13
Sequence
MAPFLRIAFNSYELGSLQAEDEANQPFCAVKMKEALSTERGKTLVQKKPTMYPEWKSTFD
AHIYEGRVIQIVLMRAAEEPVSEVTVGVSVLAERCKKNNGKAEFWLDLQPQAKVLMSVQY
FLEDVDCKQSMRSEDEAKFPTMNRRGAIKQAKIHYIKNHEFIATFFGQPTFCSVCKDFVW
GLNKQGYKCRQCNAAIHKKCIDKIIGRCTGTAANSRDTIFQKERFNIDMPHRFKVHNYMS
PTFCDHCGSLLWGLVKQGLKCEDCGMNVHHKCREKVANLCGINQKLLAEALNQVTQRASR
RSDSASSEPVGIYQGFEKKTGVAGEDMQDNSGTYGKIWEGSSKCNINNFIFHKVLGKGSF
GKVLLGELKGRGEYFAIKALKKDVVLIDDDVECTMVEKRVLTLAAENPFLTHLICTFQTK
DHLFFVMEFLNGGDLMYHIQDKGRFELYRATFYAAEIMCGLQFLHSKGIIYRDLKLDNVL
LDRDGHIKIADFGMCKENIFGESRASTFCGTPDYIAPEILQGLKYTFSVDWWSFGVLLYE
MLIGQSPFHGDDEDELFESIRVDTPHYPRWITKESKDILEKLFEREPTKRLGVTGNIKIH
PFFKTINWTLLEKRRLEPPFRPKVKSPRDYSNFDQEFLNEKARLSYSDKNLIDSMDQSAF
AGFSFVNPKFEHLLED
Function
Negatively regulates B cell proliferation and also has an important function in self-antigen induced B cell tolerance induction. Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis. In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53. In the case of ER stress or DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase ABL1 which trigger apoptosis independently of p53/TP53. In cytosol can trigger apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation treatment, is required for the activation of the apoptosis regulators BAX and BAK, which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and target it for degradation which is sufficient to trigger for BAX activation and apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M phases. Mediates phorbol 12-myristate 13-acetate (PMA)-induced inhibition of cell cycle progression at G1/S phase by up-regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint activation. Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1. Is highly expressed in a number of cancer cells and promotes cell survival and resistance against chemotherapeutic drugs by inducing cyclin D1 (CCND1) and hyperphosphorylation of RB1, and via several pro-survival pathways, including NF-kappa-B, AKT1 and MAPK1/3 (ERK1/2). Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In N-formyl-methionyl-leucyl-phenylalanine (fMLP)-treated cells, is required for NCF1 (p47-phox) phosphorylation and activation of NADPH oxidase activity, and regulates TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling pathways. May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA. In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation. Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule secretion, whereas it negatively regulates CD36/GP4-mediated granule release. Phosphorylates MUC1 in the C-terminal and regulates the interaction between MUC1 and beta-catenin. The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion. Phosphorylates ELAVL1 in response to angiotensin-2 treatment. Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor-initiated cell death, is involved in tumor suppression as well as survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses.
KEGG Pathway
Chemokine signaling pathway (hsa04062 )
Vascular smooth muscle contraction (hsa04270 )
Tight junction (hsa04530 )
Fc epsilon RI signaling pathway (hsa04664 )
Fc gamma R-mediated phagocytosis (hsa04666 )
Neurotrophin signaling pathway (hsa04722 )
Inflammatory mediator regulation of TRP channels (hsa04750 )
GnRH signaling pathway (hsa04912 )
Estrogen signaling pathway (hsa04915 )
Type II diabetes mellitus (hsa04930 )
Reactome Pathway
Calmodulin induced events (R-HSA-111933 )
Effects of PIP2 hydrolysis (R-HSA-114508 )
DAG and IP3 signaling (R-HSA-1489509 )
Role of phospholipids in phagocytosis (R-HSA-2029485 )
G alpha (z) signalling events (R-HSA-418597 )
HuR (ELAVL1) binds and stabilizes mRNA (R-HSA-450520 )
VEGFR2 mediated cell proliferation (R-HSA-5218921 )
CLEC7A (Dectin-1) signaling (R-HSA-5607764 )
Interferon gamma signaling (R-HSA-877300 )
Apoptotic cleavage of cellular proteins (R-HSA-111465 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
1 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
KAI-9803 DMELJDI Acute myocardial infarction BA41 Phase 1/2 [1]
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3 Discontinued Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
AD 198 DMJFY2I N. A. N. A. Terminated [2]
LY-317644 DMM20PI N. A. N. A. Terminated [3]
RO-320432 DMFZ1YW N. A. N. A. Terminated [4]
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20 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
13-Acetylphorbol DMJ2T7P Discovery agent N.A. Investigative [5]
2,3,3-Triphenyl-acrylonitrile DM7H34U Discovery agent N.A. Investigative [6]
2-(4-Hydroxy-phenyl)-3,3-diphenyl-acrylonitrile DMNGW1A Discovery agent N.A. Investigative [6]
3,3-Bis-(4-hydroxy-phenyl)-2-phenyl-acrylonitrile DMO51QG Discovery agent N.A. Investigative [6]
3,3-Bis-(4-methoxy-phenyl)-2-phenyl-acrylonitrile DMZPYN2 Discovery agent N.A. Investigative [6]
3-(4-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile DME5238 Discovery agent N.A. Investigative [6]
4-cycloheptyliden(4-hydroxyphenyl)methylphenol DM4LIUC Discovery agent N.A. Investigative [6]
4-cyclohexyliden(4-hydroxyphenyl)methylphenol DM8BLK2 Discovery agent N.A. Investigative [6]
4-[1-(4-hydroxyphenyl)-3-methyl-1-butenyl]phenol DM8IYG1 Discovery agent N.A. Investigative [6]
INDOLACTUM DMP543H Discovery agent N.A. Investigative [7]
Ingenol-3-bezoate DM487FU Discovery agent N.A. Investigative [8]
LY-326449 DMN53M4 Discovery agent N.A. Investigative [9]
Phorbol 12,13-butyrate DMZWTY7 Discovery agent N.A. Investigative [10]
PROSTRATIN DM1HMJ5 Human immunodeficiency virus infection 1C62 Investigative [11]
RO-316233 DMAGLPW Discovery agent N.A. Investigative [12]
Ro-32-0557 DMPVKEA Discovery agent N.A. Investigative [4]
THYMELEATOXIN DMUDGSN Discovery agent N.A. Investigative [8]
[2,2':5',2'']Terthiophen-4-yl-methanol DMRQC1F Discovery agent N.A. Investigative [13]
[2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde DMWDNLI Discovery agent N.A. Investigative [13]
[2,2':5',2'']Terthiophene-4-carbaldehyde DM2S5EJ Discovery agent N.A. Investigative [13]
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⏷ Show the Full List of 20 Investigative Drug(s)

Molecular Expression Atlas (MEA) of This DTT

Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This DTT
Disease Name ICD 11 Studied Tissue p-value Fold-Change Z-score
Breast cancer 2C82 Breast tissue 1.25E-22 0.59 0.82
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References

1 PKC delta and epsilon in drug targeting and therapeutics. Recent Pat DNA Gene Seq. 2009;3(2):96-101.
2 Novel extranuclear-targeted anthracyclines override the antiapoptotic functions of Bcl-2 and target protein kinase C pathways to induce apoptosis. Mol Cancer Ther. 2002 May;1(7):469-81.
3 Synthesis of bisindolylmaleimide macrocycles, Bioorg. Med. Chem. Lett. 5(18):2093-2096 (1995).
4 Bisindolylmaleimide inhibitors of protein kinase C. Further conformational restriction of a tertiary amine side chain, Bioorg. Med. Chem. Lett. 4(11):1303-1308 (1994).
5 The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
6 Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicate... J Med Chem. 1992 Feb 7;35(3):573-83.
7 Structural basis of RasGRP binding to high-affinity PKC ligands. J Med Chem. 2002 Feb 14;45(4):853-60.
8 Structural basis of binding of high-affinity ligands to protein kinase C: prediction of the binding modes through a new molecular dynamics method a... J Med Chem. 2001 May 24;44(11):1690-701.
9 (S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H... J Med Chem. 1996 Jul 5;39(14):2664-71.
10 Conformationally constrained analogues of diacylglycerol (DAG). 28. DAG-dioxolanones reveal a new additional interaction site in the C1b domain of ... J Med Chem. 2007 Jul 26;50(15):3465-81.
11 A nonpromoting phorbol from the samoan medicinal plant Homalanthus nutans inhibits cell killing by HIV-1. J Med Chem. 1992 May 29;35(11):1978-86.
12 Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem. 1992 Jan;35(1):177-84.
13 Novel protein kinase C inhibitors: synthesis and PKC inhibition of beta-substituted polythiophene derivatives. Bioorg Med Chem Lett. 1999 Aug 2;9(15):2279-82.