Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Protein kinase C gamma (PRKCG)
• Synonyms: PRKCG; PKCG; PKC-gamma
• Gene Name: PRKCG
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: KPCG_HUMAN
• TTD ID: T47107
• EC Number: EC 2.7.11.13
• Sequence:
  MAGLGPGVGDSEGGPRPLFCRKGALRQKVVHEVKSHKFTARFFKQPTFCSHCTDFIWGIG
  KQGLQCQVCSFVVHRRCHEFVTFECPGAGKGPQTDDPRNKHKFRLHSYSSPTFCDHCGSL
  LYGLVHQGMKCSCCEMNVHRRCVRSVPSLCGVDHTERRGRLQLEIRAPTADEIHVTVGEA
  RNLIPMDPNGLSDPYVKLKLIPDPRNLTKQKTRTVKATLNPVWNETFVFNLKPGDVERRL
  SVEVWDWDRTSRNDFMGAMSFGVSELLKAPVDGWYKLLNQEEGEYYNVPVADADNCSLLQ
  KFEACNYPLELYERVRMGPSSSPIPSPSPSPTDPKRCFFGASPGRLHISDFSFLMVLGKG
  SFGKVMLAERRGSDELYAIKILKKDVIVQDDDVDCTLVEKRVLALGGRGPGGRPHFLTQL
  HSTFQTPDRLYFVMEYVTGGDLMYHIQQLGKFKEPHAAFYAAEIAIGLFFLHNQGIIYRD
  LKLDNVMLDAEGHIKITDFGMCKENVFPGTTTRTFCGTPDYIAPEIIAYQPYGKSVDWWS
  FGVLLYEMLAGQPPFDGEDEEELFQAIMEQTVTYPKSLSREAVAICKGFLTKHPGKRLGS
  GPDGEPTIRAHGFFRWIDWERLERLEIPPPFRPRPCGRSGENFDKFFTRAAPALTPPDRL
  VLASIDQADFQGFTYVNPDFVHPDARSPTSPVPVPVM
• Function: Calcium-activated, phospholipid-and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays diverse roles in neuronal cells and eye tissues, such as regulation of the neuronal receptors GRIA4/GLUR4 and GRIN1/NMDAR1, modulation of receptors and neuronal functions related to sensitivity to opiates, pain and alcohol, mediation of synaptic function and cell survival after ischemia, and inhibition of gap junction activity after oxidative stress. Binds and phosphorylates GRIA4/GLUR4 glutamate receptor and regulates its function by increasing plasma membrane-associated GRIA4 expression. In primary cerebellar neurons treated with the agonist 3,5-dihyidroxyphenylglycine, functions downstream of the metabotropic glutamate receptor GRM5/MGLUR5 and phosphorylates GRIN1/NMDAR1 receptor which plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. May be involved in the regulation of hippocampal long-term potentiation (LTP), but may be not necessary for the process of synaptic plasticity. May be involved in desensitization of mu-type opioid receptor-mediated G-protein activation in the spinal cord, and may be critical for the development and/or maintenance ofmorphine-induced reinforcing effects in the limbic forebrain. May modulate the functionality of mu-type-opioid receptors by participating in a signaling pathway which leads to the phosphorylation anddegradation of opioid receptors. May also contributes to chronic morphine-induced changes in nociceptive processing. Plays a role in neuropathic pain mechanisms and contributes to the maintenance of the allodynia pain produced by peripheral inflammation. Plays an important role in initial sensitivity and tolerance to ethanol, by mediating the behavioral effects of ethanol as well as the effects of this drug on the GABA(A) receptors. During and after cerebral ischemia modulate neurotransmission and cell survival in synaptic membranes, and is involved in insulin-induced inhibition of necrosis, an important mechanism for minimizing ischemic injury. Required for the elimination of multiple climbing fibers during innervation of Purkinje cells in developing cerebellum. Is activated in lens epithelial cells upon hydrogen peroxide treatment, and phosphorylates connexin-43 (GJA1/CX43), resulting in disassembly of GJA1 gap junction plaques and inhibition of gap junction activity which could provide a protective effect against oxidative stress. Phosphorylates p53/TP53 and promotes p53/TP53-dependent apoptosis in response to DNA damage. Involved in the phase resetting of the cerebral cortex circadian clock during temporally restricted feeding. Stabilizes the core clock component ARNTL/BMAL1 by interfering with its ubiquitination, thus suppressing its degradation, resultingin phase resetting of the cerebral cortex clock.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  ErbB signaling pathway (hsa04012)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  Calcium signaling pathway (hsa04020)
  HIF-1 signaling pathway (hsa04066)
  Phosphatidylinositol signaling system (hsa04070)
  Sphingolipid signaling pathway (hsa04071)
  mTOR signaling pathway (hsa04150)
  Vascular smooth muscle contraction (hsa04270)
  Wnt signaling pathway (hsa04310)
  VEGF signaling pathway (hsa04370)
  Focal adhesion (hsa04510)
  Tight junction (hsa04530)
  Gap junction (hsa04540)
  Natural killer cell mediated cytotoxicity (hsa04650)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Leukocyte transendothelial migration (hsa04670)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocannabinoid signaling (hsa04723)
  Glutamatergic synapse (hsa04724)
  Cholinergic synapse (hsa04725)
  Serotonergic synapse (hsa04726)
  GABAergic synapse (hsa04727)
  Dopaminergic synapse (hsa04728)
  Long-term depression (hsa04730)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin secretion (hsa04911)
  Melanogenesis (hsa04916)
  Thyroid hormone synthesis (hsa04918)
  Thyroid hormone signaling pathway (hsa04919)
  Oxytocin signaling pathway (hsa04921)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Amphetamine addiction (hsa05031)
  Morphine addiction (hsa05032)
  Vibrio cholerae infection (hsa05110)
  African trypanosomiasis (hsa05143)
  Amoebiasis (hsa05146)
  Hepatitis B (hsa05161)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Glioma (hsa05214)
  Non-small cell lung cancer (hsa05223)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Disinhibition of SNARE formation (R-HSA-114516)
  Trafficking of GluR2-containing AMPA receptors (R-HSA-416993)
  G alpha (z) signalling events (R-HSA-418597)
  WNT5A-dependent internalization of FZD4 (R-HSA-5099900)
  Response to elevated platelet cytosolic Ca2+ (R-HSA-76005)
  Calmodulin induced events (R-HSA-111933)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Midostaurin	DMI6E0R	Acute myeloid leukaemia	2A60	Approved	[1]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BALANOL	DMDLN9E	N. A.	N. A.	Terminated	[2]
LY-317644	DMM20PI	N. A.	N. A.	Terminated	[3]
RO-320432	DMFZ1YW	N. A.	N. A.	Terminated	[4]

25 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(-)-Cercosporamide	DMJ249P	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-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione	DMDO175	Discovery agent	N.A.	Investigative	[7]
3,4-diphenyl-1H-pyrrole-2,5-dione	DMPK6YT	Discovery agent	N.A.	Investigative	[7]
3-(4-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile	DME5238	Discovery agent	N.A.	Investigative	[6]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione	DMGC7RY	Discovery agent	N.A.	Investigative	[7]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione	DM3EV9N	Discovery agent	N.A.	Investigative	[7]
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-cyclopentyliden(4-hydroxyphenyl)methylphenol	DM7LN53	Discovery agent	N.A.	Investigative	[6]
4-[1-(4-hydroxyphenyl)-3-methyl-1-butenyl]phenol	DM8IYG1	Discovery agent	N.A.	Investigative	[6]
8-Octyl-benzolactam-V9	DM4Z15M	Discovery agent	N.A.	Investigative	[8]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[9]
Go 6983	DMKVTZN	Discovery agent	N.A.	Investigative	[10]
LY-326449	DMN53M4	Discovery agent	N.A.	Investigative	[11]
Monoctanoin component C	DM31YGM	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	[4]
[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
Acute myelocytic leukaemia	2C82	Bone marrow	9.42E-04	0.06	0.3
Colon cancer	2C82	Colon tissue	2.49E-01	-0.02	-0.1
Breast cancer	2C82	Breast tissue	5.25E-10	-0.07	-0.35

References

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• [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] Synthesis and characterization of the second cysteine-rich region of mouse skin PKCGh, Bioorg. Med. Chem. Lett. 6(4):353-356 (1996).
• [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.
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• [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.