Target Information
Target General Infomation | |||||
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Target ID |
T47107
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Former ID |
TTDC00015
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Target Name |
Protein kinase C gamma type
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Gene Name |
PRKCG
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Synonyms |
PKC-gamma; PKCG; PRKCG
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Target Type |
Successful
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Disease | Acute myeloid leukemia [ICD9: 205; ICD10: C92.0] | ||||
Breast cancer; Colorectal cancer [ICD9: 153, 154, 174, 175; ICD10: C18-C21, C50] | |||||
Colon cancer; Breast cancer; CLL; AML; GIST [ICD9: 140-199, 150-159, 200, 202, 202.8, 204.1, 205.0, 210-229; ICD10: C00-C75, C15-C26, C7A, C7B, C81-C86, C82-C85, C91.1, C92.0, D10-D36, D3A] | |||||
Human immunodeficiency virus infection [ICD9: 279.3; ICD10: B20-B26] | |||||
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 (By similarity). 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 (By similarity).
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BioChemical Class |
Kinase
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Target Validation |
T47107
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UniProt ID | |||||
EC Number |
EC 2.7.11.13
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Sequence |
MAGLGPGVGDSEGGPRPLFCRKGALRQKVVHEVKSHKFTARFFKQPTFCSHCTDFIWGIG
KQGLQCQVCSFVVHRRCHEFVTFECPGAGKGPQTDDPRNKHKFRLHSYSSPTFCDHCGSL LYGLVHQGMKCSCCEMNVHRRCVRSVPSLCGVDHTERRGRLQLEIRAPTADEIHVTVGEA RNLIPMDPNGLSDPYVKLKLIPDPRNLTKQKTRTVKATLNPVWNETFVFNLKPGDVERRL SVEVWDWDRTSRNDFMGAMSFGVSELLKAPVDGWYKLLNQEEGEYYNVPVADADNCSLLQ KFEACNYPLELYERVRMGPSSSPIPSPSPSPTDPKRCFFGASPGRLHISDFSFLMVLGKG SFGKVMLAERRGSDELYAIKILKKDVIVQDDDVDCTLVEKRVLALGGRGPGGRPHFLTQL HSTFQTPDRLYFVMEYVTGGDLMYHIQQLGKFKEPHAAFYAAEIAIGLFFLHNQGIIYRD LKLDNVMLDAEGHIKITDFGMCKENVFPGTTTRTFCGTPDYIAPEIIAYQPYGKSVDWWS FGVLLYEMLAGQPPFDGEDEEELFQAIMEQTVTYPKSLSREAVAICKGFLTKHPGKRLGS GPDGEPTIRAHGFFRWIDWERLERLEIPPPFRPRPCGRSGENFDKFFTRAAPALTPPDRL VLASIDQADFQGFTYVNPDFVHPDARSPTSPVPVPVM |
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Drugs and Mode of Action | |||||
Drug(s) | Midostaurin | Drug Info | Approved | Acute myeloid leukemia | [889446] |
Midostaurin | Drug Info | Phase 2 | Colon cancer; Breast cancer; CLL; AML; GIST | [537114], [541045] | |
Midostaurin | Drug Info | Phase 1 | Breast cancer; Colorectal cancer | [537114], [541045] | |
BALANOL | Drug Info | Terminated | Discovery agent | [542983], [545589] | |
LY-317644 | Drug Info | Terminated | Discovery agent | [546513] | |
RO-320432 | Drug Info | Terminated | Discovery agent | [541291], [545975] | |
Inhibitor | (-)-Cercosporamide | Drug Info | [529887] | ||
2,3,3-Triphenyl-acrylonitrile | Drug Info | [528755] | |||
2-(4-Hydroxy-phenyl)-3,3-diphenyl-acrylonitrile | Drug Info | [528755] | |||
3,3-Bis-(4-hydroxy-phenyl)-2-phenyl-acrylonitrile | Drug Info | [528755] | |||
3,3-Bis-(4-methoxy-phenyl)-2-phenyl-acrylonitrile | Drug Info | [528755] | |||
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione | Drug Info | [528032] | |||
3,4-diphenyl-1H-pyrrole-2,5-dione | Drug Info | [528032] | |||
3-(4-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile | Drug Info | [528755] | |||
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione | Drug Info | [528032] | |||
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione | Drug Info | [528032] | |||
4-cycloheptyliden(4-hydroxyphenyl)methylphenol | Drug Info | [528755] | |||
4-cyclohexyliden(4-hydroxyphenyl)methylphenol | Drug Info | [528755] | |||
4-cyclopentyliden(4-hydroxyphenyl)methylphenol | Drug Info | [528755] | |||
4-[1-(4-hydroxyphenyl)-3-methyl-1-butenyl]phenol | Drug Info | [528755] | |||
8-Octyl-benzolactam-V9 | Drug Info | [528158] | |||
BALANOL | Drug Info | [551285] | |||
GF-109203 | Drug Info | [529049] | |||
Go 6983 | Drug Info | [534191] | |||
Indolocarbazole analogue | Drug Info | [526234] | |||
LY-317644 | Drug Info | [551283] | |||
LY-326449 | Drug Info | [534154] | |||
Midostaurin | Drug Info | [536474], [537142] | |||
Monoctanoin component C | Drug Info | [551310] | |||
PROSTRATIN | Drug Info | [527606] | |||
RO-316233 | Drug Info | [528701] | |||
Ro-32-0557 | Drug Info | [551264] | |||
RO-320432 | Drug Info | [551264] | |||
[2,2':5',2'']Terthiophen-4-yl-methanol | Drug Info | [525575] | |||
[2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde | Drug Info | [525575] | |||
[2,2':5',2'']Terthiophene-4-carbaldehyde | Drug Info | [525575] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | MAPK signaling pathway | ||||
ErbB signaling pathway | |||||
Ras signaling pathway | |||||
Rap1 signaling pathway | |||||
Calcium signaling pathway | |||||
HIF-1 signaling pathway | |||||
Phosphatidylinositol signaling system | |||||
Sphingolipid signaling pathway | |||||
mTOR signaling pathway | |||||
Vascular smooth muscle contraction | |||||
Wnt signaling pathway | |||||
VEGF signaling pathway | |||||
Focal adhesion | |||||
Tight junction | |||||
Gap junction | |||||
Natural killer cell mediated cytotoxicity | |||||
Fc gamma R-mediated phagocytosis | |||||
Leukocyte transendothelial migration | |||||
Circadian entrainment | |||||
Long-term potentiation | |||||
Retrograde endocannabinoid signaling | |||||
Glutamatergic synapse | |||||
Cholinergic synapse | |||||
Serotonergic synapse | |||||
GABAergic synapse | |||||
Dopaminergic synapse | |||||
Long-term depression | |||||
Inflammatory mediator regulation of TRP channels | |||||
Insulin secretion | |||||
Melanogenesis | |||||
Thyroid hormone synthesis | |||||
Thyroid hormone signaling pathway | |||||
Oxytocin signaling pathway | |||||
Aldosterone-regulated sodium reabsorption | |||||
Endocrine and other factor-regulated calcium reabsorption | |||||
Salivary secretion | |||||
Gastric acid secretion | |||||
Pancreatic secretion | |||||
Amphetamine addiction | |||||
Morphine addiction | |||||
Vibrio cholerae infection | |||||
African trypanosomiasis | |||||
Amoebiasis | |||||
Hepatitis B | |||||
Pathways in cancer | |||||
Proteoglycans in cancer | |||||
MicroRNAs in cancer | |||||
Glioma | |||||
Non-small cell lung cancer | |||||
Choline metabolism in cancer | |||||
PANTHER Pathway | Alpha adrenergic receptor signaling pathway | ||||
Alzheimer disease-amyloid secretase pathway | |||||
Angiogenesis | |||||
Apoptosis signaling pathway | |||||
EGF receptor signaling pathway | |||||
Endothelin signaling pathway | |||||
FGF signaling pathway | |||||
Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway | |||||
Muscarinic acetylcholine receptor 1 and 3 signaling pathway | |||||
VEGF signaling pathway | |||||
Wnt signaling pathway | |||||
5HT2 type receptor mediated signaling pathway | |||||
Histamine H1 receptor mediated signaling pathway | |||||
Oxytocin receptor mediated signaling pathway | |||||
Thyrotropin-releasing hormone receptor signaling pathway | |||||
Pathway Interaction Database | Endothelins | ||||
Thromboxane A2 receptor signaling | |||||
Role of Calcineurin-dependent NFAT signaling in lymphocytes | |||||
Retinoic acid receptors-mediated signaling | |||||
IL8- and CXCR2-mediated signaling events | |||||
PAR1-mediated thrombin signaling events | |||||
IL8- and CXCR1-mediated signaling events | |||||
Reactome | Calmodulin induced events | ||||
Disinhibition of SNARE formation | |||||
Trafficking of GluR2-containing AMPA receptors | |||||
G alpha (z) signalling events | |||||
WNT5A-dependent internalization of FZD4 | |||||
Response to elevated platelet cytosolic Ca2+ | |||||
WikiPathways | Calcium Regulation in the Cardiac Cell | ||||
Wnt Signaling Pathway | |||||
Wnt Signaling Pathway and Pluripotency | |||||
MAPK Signaling Pathway | |||||
Wnt Signaling Pathway Netpath | |||||
G Protein Signaling Pathways | |||||
Myometrial Relaxation and Contraction Pathways | |||||
DAG and IP3 signaling | |||||
Signaling Pathways in Glioblastoma | |||||
miRs in Muscle Cell Differentiation | |||||
Opioid Signalling | |||||
Response to elevated platelet cytosolic Ca2+ | |||||
References | |||||
Ref 541045 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5702). | ||||
Ref 541291 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6034). | ||||
Ref 542983 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8142). | ||||
Ref 545589 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003814) | ||||
Ref 545975 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005586) | ||||
Ref 525575 | Bioorg Med Chem Lett. 1999 Aug 2;9(15):2279-82.Novel protein kinase C inhibitors: synthesis and PKC inhibition of beta-substituted polythiophene derivatives. | ||||
Ref 526234 | Bioorg Med Chem Lett. 2002 Jan 21;12(2):147-50.Mixed lineage kinase activity of indolocarbazole analogues. | ||||
Ref 527606 | J Med Chem. 1992 May 29;35(11):1978-86.A nonpromoting phorbol from the samoan medicinal plant Homalanthus nutans inhibits cell killing by HIV-1. | ||||
Ref 528032 | J Med Chem. 2006 Feb 23;49(4):1271-81.Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. | ||||
Ref 528158 | J Med Chem. 2006 May 4;49(9):2681-8.Design and synthesis of 8-octyl-benzolactam-V9, a selective activator for protein kinase C epsilon and eta. | ||||
Ref 528701 | J Med Chem. 1992 Jan;35(1):177-84.Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. | ||||
Ref 528755 | J Med Chem. 1992 Feb 7;35(3):573-83.Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicated in estrogen receptor binding, protein kinase C activity, and MCF7 cell proliferation. | ||||
Ref 529049 | J Biol Chem. 2007 Nov 9;282(45):33052-63. Epub 2007 Sep 17.Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. | ||||
Ref 529887 | Bioorg Med Chem Lett. 2009 Feb 1;19(3):724-6. Epub 2008 Dec 11.(-)-Cercosporamide derivatives as novel antihyperglycemic agents. | ||||
Ref 534154 | J Med Chem. 1996 Jul 5;39(14):2664-71.(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)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C beta. | ||||
Ref 534191 | Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett. 1996 Aug 26;392(2):77-80. | ||||
Ref 536474 | A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22. | ||||
Ref 537142 | CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes. Clin Cancer Res. 2009 Apr 1;15(7):2238-47. Epub 2009 Mar 10. | ||||
Ref 551264 | Bisindolylmaleimide inhibitors of protein kinase C. Further conformational restriction of a tertiary amine side chain, Bioorg. Med. Chem. Lett. 4(11):1303-1308 (1994). | ||||
Ref 551283 | Synthesis of bisindolylmaleimide macrocycles, Bioorg. Med. Chem. Lett. 5(18):2093-2096 (1995). |
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