Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT7A1BO)

• DTT Name: PKC-delta messenger RNA (PRKCD mRNA)
• Synonyms: nPKC-delta (mRNA); Tyrosine-protein kinase PRKCD (mRNA); SDK1 (mRNA); Protein kinase C delta type catalytic subunit (mRNA); Protein kinase C delta type (mRNA); Protein Kinase C delta (mRNA); PKC-delta (mRNA)
• Gene Name: PRKCD
• DTT Type: Literature-reported target; [1]
• Related Disease: Human immunodeficiency virus disease [ICD-11: 1C60-1C62]
• BioChemical Class: mRNA target
• UniProt ID: KPCD_HUMAN
• TTD ID: T49368
• 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 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BALANOL	DMDLN9E	N. A.	N. A.	Terminated	[1]

11 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
8-Octyl-benzolactam-V9	DM4Z15M	Discovery agent	N.A.	Investigative	[2]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[3]
Diheptan-3-yl 5-(hydroxymethyl)isophthalate	DMBAY7P	Discovery agent	N.A.	Investigative	[4]
Dihexan-3-yl 5-(hydroxymethyl)isophthalate	DM8TBQ9	Discovery agent	N.A.	Investigative	[4]
Go 6983	DMKVTZN	Discovery agent	N.A.	Investigative	[5]
ISIS 10303	DM205TE	Discovery agent	N.A.	Investigative	[6]
ISIS 10310	DMT6H9S	Discovery agent	N.A.	Investigative	[6]
ISIS 10311	DMQ3KUV	Discovery agent	N.A.	Investigative	[6]
ISIS 17252	DMW40NK	Discovery agent	N.A.	Investigative	[7]
LY-326449	DMN53M4	Discovery agent	N.A.	Investigative	[8]
PROSTRATIN	DM1HMJ5	Human immunodeficiency virus infection	1C62	Investigative	[9]

References

• [1] Evaluation of differential hypoxic cytotoxicity and electrochemical studies of nitro 5-deazaflavins, Bioorg. Med. Chem. Lett. 5(18):2155-2160 (1995).
• [2] Design and synthesis of 8-octyl-benzolactam-V9, a selective activator for protein kinase C epsilon and eta. J Med Chem. 2006 May 4;49(9):2681-8.
• [3] Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2... J Biol Chem. 2007 Nov 9;282(45):33052-63.
• [4] Design, synthesis, and biological activity of isophthalic acid derivatives targeted to the C1 domain of protein kinase C. J Med Chem. 2009 Jul 9;52(13):3969-81.
• [5] Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett. 1996 Aug 26;392(2):77-80.
• [6] US patent application no. 5,959,096, Antisense oligonucleotides against human protein kinase C.
• [7] US patent application no. 6,235,723, Antisense oligonucleotide modulation of human protein kinase C-.delta. expression.
• [8] (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.
• [9] 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.