Details of the Drug Therapeutic Target (DTT)

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]
• Related Disease: Myocardial infarction [ICD-11: BA41-BA43]
• BioChemical Class: Kinase
• UniProt ID: KPCD_HUMAN
• TTD ID: T44861
• 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

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], [2], [3]

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	[4]
LY-317644	DMM20PI	N. A.	N. A.	Terminated	[5]
RO-320432	DMFZ1YW	N. A.	N. A.	Terminated	[6]

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	[7]
2,3,3-Triphenyl-acrylonitrile	DM7H34U	Discovery agent	N.A.	Investigative	[8]
2-(4-Hydroxy-phenyl)-3,3-diphenyl-acrylonitrile	DMNGW1A	Discovery agent	N.A.	Investigative	[8]
3,3-Bis-(4-hydroxy-phenyl)-2-phenyl-acrylonitrile	DMO51QG	Discovery agent	N.A.	Investigative	[8]
3,3-Bis-(4-methoxy-phenyl)-2-phenyl-acrylonitrile	DMZPYN2	Discovery agent	N.A.	Investigative	[8]
3-(4-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile	DME5238	Discovery agent	N.A.	Investigative	[8]
4-cycloheptyliden(4-hydroxyphenyl)methylphenol	DM4LIUC	Discovery agent	N.A.	Investigative	[8]
4-cyclohexyliden(4-hydroxyphenyl)methylphenol	DM8BLK2	Discovery agent	N.A.	Investigative	[8]
4-[1-(4-hydroxyphenyl)-3-methyl-1-butenyl]phenol	DM8IYG1	Discovery agent	N.A.	Investigative	[8]
INDOLACTUM	DMP543H	Discovery agent	N.A.	Investigative	[9]
Ingenol-3-bezoate	DM487FU	Discovery agent	N.A.	Investigative	[10]
LY-326449	DMN53M4	Discovery agent	N.A.	Investigative	[11]
Phorbol 12,13-butyrate	DMZWTY7	Discovery agent	N.A.	Investigative	[12]
PROSTRATIN	DM1HMJ5	Human immunodeficiency virus infection	1C62	Investigative	[13]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[14]
Ro-32-0557	DMPVKEA	Discovery agent	N.A.	Investigative	[6]
THYMELEATOXIN	DMUDGSN	Discovery agent	N.A.	Investigative	[10]
[2,2':5',2'']Terthiophen-4-yl-methanol	DMRQC1F	Discovery agent	N.A.	Investigative	[15]
[2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde	DMWDNLI	Discovery agent	N.A.	Investigative	[15]
[2,2':5',2'']Terthiophene-4-carbaldehyde	DM2S5EJ	Discovery agent	N.A.	Investigative	[15]

Molecular Expression Atlas (MEA) 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

References

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• [2] Letter by Metzler et al regarding article, "Intracoronary KAI-9803 as an adjunct to primary coronary intervention for acute ST-segment elevation myocardial infarction". Circulation. 2008 Jul 22;118(4):e80.
• [3] Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation. 2008 Feb 19;117(7):886-96.
• [4] 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.
• [5] Synthesis of bisindolylmaleimide macrocycles, Bioorg. Med. Chem. Lett. 5(18):2093-2096 (1995).
• [6] Bisindolylmaleimide inhibitors of protein kinase C. Further conformational restriction of a tertiary amine side chain, Bioorg. Med. Chem. Lett. 4(11):1303-1308 (1994).
• [7] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [8] 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.
• [9] Structural basis of RasGRP binding to high-affinity PKC ligands. J Med Chem. 2002 Feb 14;45(4):853-60.
• [10] 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.
• [11] (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.
• [12] 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.
• [13] 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.
• [14] Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem. 1992 Jan;35(1):177-84.
• [15] 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.