Details of the Drug Therapeutic Target (DTT)

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

DTT Name	Protein kinase C beta (PRKCB)
Synonyms	Protein kinase C beta type; PRKCB1; PKCB; PKC-beta; PKC-B
Gene Name	PRKCB
DTT Type	Clinical trial target	[1]
BioChemical Class	Kinase
UniProt ID	KPCB_HUMAN
TTD ID	T40276
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
EC Number	EC 2.7.11.13
Sequence	MADPAAGPPPSEGEESTVRFARKGALRQKNVHEVKNHKFTARFFKQPTFCSHCTDFIWGF GKQGFQCQVCCFVVHKRCHEFVTFSCPGADKGPASDDPRSKHKFKIHTYSSPTFCDHCGS LLYGLIHQGMKCDTCMMNVHKRCVMNVPSLCGTDHTERRGRIYIQAHIDRDVLIVLVRDA KNLVPMDPNGLSDPYVKLKLIPDPKSESKQKTKTIKCSLNPEWNETFRFQLKESDKDRRL SVEIWDWDLTSRNDFMGSLSFGISELQKASVDGWFKLLSQEEGEYFNVPVPPEGSEANEE LRQKFERAKISQGTKVPEEKTTNTVSKFDNNGNRDRMKLTDFNFLMVLGKGSFGKVMLSE RKGTDELYAVKILKKDVVIQDDDVECTMVEKRVLALPGKPPFLTQLHSCFQTMDRLYFVM EYVNGGDLMYHIQQVGRFKEPHAVFYAAEIAIGLFFLQSKGIIYRDLKLDNVMLDSEGHI KIADFGMCKENIWDGVTTKTFCGTPDYIAPEIIAYQPYGKSVDWWAFGVLLYEMLAGQAP FEGEDEDELFQSIMEHNVAYPKSMSKEAVAICKGLMTKHPGKRLGCGPEGERDIKEHAFF RYIDWEKLERKEIQPPYKPKARDKRDTSNFDKEFTRQPVELTPTDKLFIMNLDQNEFAGF SYTNPEFVINV
Function	Plays a key role in B-cell activation by regulating BCR-induced NF-kappa-B activation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11/CARMA1 at 'Ser-559', 'Ser-644' and 'Ser-652'. Phosphorylation induces CARD11/CARMA1 association with lipid rafts and recruitment of the BCL10-MALT1 complex as well as MAP3K7/TAK1, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. Plays a direct role in the negative feedback regulation of the BCR signaling, by down-modulating BTK function via direct phosphorylation of BTK at 'Ser-180', which results in the alteration of BTK plasma membrane localization and in turn inhibition of BTK activity. Involved in apoptosis following oxidative damage: in case of oxidative conditions, specifically phosphorylates 'Ser-36' of isoform p66Shc of SHC1, leading to mitochondrial accumulation of p66Shc, where p66Shc acts as a reactive oxygen species producer. Acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and specifically mediating phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag for epigenetic transcriptional activation that prevents demethylation of histone H3 'Lys-4' (H3K4me) by LSD1/KDM1A. In insulin signaling, may function downstream of IRS1 in muscle cells and mediate insulin-dependent DNA synthesis through the RAF1-MAPK/ERK signaling cascade. May participate in the regulation of glucose transport in adipocytes by negatively modulating the insulin-stimulated translocation of the glucose transporter SLC2A4/GLUT4. Under high glucose in pancreatic beta-cells, is probably involved in the inhibition of the insulin gene transcription, via regulation of MYC expression. In endothelial cells, activation of PRKCB induces increased phosphorylation of RB1, increased VEGFA-induced cell proliferation, and inhibits PI3K/AKT-dependent nitric oxide synthase (NOS3/eNOS) regulation by insulin, which causes endothelial dysfunction. Also involved in triglyceride homeostasis. Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription. Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase involved in various cellular processes such as regulation of the B-cell receptor (BCR) signalosome, oxidative stress-induced apoptosis, androgen receptor-dependent transcription regulation, insulin signaling and endothelial cells proliferation.
KEGG Pathway	MAPK signaling pathway (hsa04010 ) ErbB signaling pathway (hsa04012 ) Ras signaling pathway (hsa04014 ) Rap1 signaling pathway (hsa04015 ) Calcium signaling pathway (hsa04020 ) Chemokine signaling pathway (hsa04062 ) NF-kappa B signaling pathway (hsa04064 ) 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 ) B cell receptor signaling pathway (hsa04662 ) Fc epsilon RI signaling pathway (hsa04664 ) 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 ) GnRH signaling pathway (hsa04912 ) 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 ) Carbohydrate digestion and absorption (hsa04973 ) Amphetamine addiction (hsa05031 ) Morphine addiction (hsa05032 ) Vibrio cholerae infection (hsa05110 ) Leishmaniasis (hsa05140 ) African trypanosomiasis (hsa05143 ) Amoebiasis (hsa05146 ) Hepatitis B (hsa05161 ) Influenza A (hsa05164 ) 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	Activation of NF-kappaB in B cells (R-HSA-1169091 ) Trafficking of GluR2-containing AMPA receptors (R-HSA-416993 ) G alpha (z) signalling events (R-HSA-418597 ) Depolymerisation of the Nuclear Lamina (R-HSA-4419969 ) WNT5A-dependent internalization of FZD4 (R-HSA-5099900 ) VEGFR2 mediated cell proliferation (R-HSA-5218921 ) Response to elevated platelet cytosolic Ca2+ (R-HSA-76005 ) Disinhibition of SNARE formation (R-HSA-114516 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DTT

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Enzastaurin	DM5H0R9	Diffuse large B-cell lymphoma	2A81	Phase 3	[1]
RUBOXISTAURIN HYDROCHLORIDE	DMQOCD8	Lymphoma	2A80-2A86	Phase 3	[2]
LY333531	DMGMC8H	Solid tumour/cancer	2A00-2F9Z	Phase 2	[3]
Sotrastaurin acetate	DME53YS	Renal transplantation	NE84	Phase 2	[4]
MS-553	DM7ER9J	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[5]
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4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Linetastine	DMF8B62	Rhinitis	FA20	Discontinued in Phase 2	[6]
BALANOL	DMDLN9E	N. A.	N. A.	Terminated	[7]
LY-317644	DMM20PI	N. A.	N. A.	Terminated	[8]
RO-320432	DMFZ1YW	N. A.	N. A.	Terminated	[9]
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23 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(-)-Cercosporamide	DMJ249P	Discovery agent	N.A.	Investigative	[10]
2,3,3-Triphenyl-acrylonitrile	DM7H34U	Discovery agent	N.A.	Investigative	[11]
2-(4-Hydroxy-phenyl)-3,3-diphenyl-acrylonitrile	DMNGW1A	Discovery agent	N.A.	Investigative	[11]
3,3-Bis-(4-hydroxy-phenyl)-2-phenyl-acrylonitrile	DMO51QG	Discovery agent	N.A.	Investigative	[11]
3,3-Bis-(4-methoxy-phenyl)-2-phenyl-acrylonitrile	DMZPYN2	Discovery agent	N.A.	Investigative	[11]
3-(1H-Indol-3-yl)-4-phenylamino-pyrrole-2,5-dione	DMP0RYB	Discovery agent	N.A.	Investigative	[12]
3-(4-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile	DME5238	Discovery agent	N.A.	Investigative	[11]
4-cycloheptyliden(4-hydroxyphenyl)methylphenol	DM4LIUC	Discovery agent	N.A.	Investigative	[11]
4-cyclohexyliden(4-hydroxyphenyl)methylphenol	DM8BLK2	Discovery agent	N.A.	Investigative	[11]
4-cyclopentyliden(4-hydroxyphenyl)methylphenol	DM7LN53	Discovery agent	N.A.	Investigative	[11]
4-[1-(4-hydroxyphenyl)-3-methyl-1-butenyl]phenol	DM8IYG1	Discovery agent	N.A.	Investigative	[11]
Go 6983	DMKVTZN	Discovery agent	N.A.	Investigative	[13]
K00248	DMWZJG6	Discovery agent	N.A.	Investigative	[12]
LY-326449	DMN53M4	Discovery agent	N.A.	Investigative	[14]
O-Phosphoethanolamine	DM3O9YW	N. A.	N. A.	Investigative	[15]
PROSTRATIN	DM1HMJ5	Human immunodeficiency virus infection	1C62	Investigative	[16]
PUNICAFOLIN	DM7CWQY	Discovery agent	N.A.	Investigative	[17]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[18]
Ro-32-0557	DMPVKEA	Discovery agent	N.A.	Investigative	[9]
TANNIN	DMTFHRI	Discovery agent	N.A.	Investigative	[17]
[2,2':5',2'']Terthiophen-4-yl-methanol	DMRQC1F	Discovery agent	N.A.	Investigative	[19]
[2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde	DMWDNLI	Discovery agent	N.A.	Investigative	[19]
[2,2':5',2'']Terthiophene-4-carbaldehyde	DM2S5EJ	Discovery agent	N.A.	Investigative	[19]
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⏷ Show the Full List of 23 Investigative Drug(s)

References

1	The oral protein-kinase C beta inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines. Leuk Lymphoma. 2008 Jul;49(7):1374-83.
2	Ruboxistaurin: LY 333531. Drugs R D. 2007;8(3):193-9.
3	Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes. 2003 Feb;52(2):512-8.
4	Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
5	ClinicalTrials.gov (NCT03492125) A Study Of The Selective PKC-beta Inhibitor MS- 553. U.S. National Institutes of Health.
6	Potential new medical therapies for diabetic retinopathy: protein kinase C inhibitors. Am J Ophthalmol. 2002 May;133(5):693-8.
7	Evaluation of differential hypoxic cytotoxicity and electrochemical studies of nitro 5-deazaflavins, Bioorg. Med. Chem. Lett. 5(18):2155-2160 (1995).
8	Synthesis of bisindolylmaleimide macrocycles, Bioorg. Med. Chem. Lett. 5(18):2093-2096 (1995).
9	Bisindolylmaleimide inhibitors of protein kinase C. Further conformational restriction of a tertiary amine side chain, Bioorg. Med. Chem. Lett. 4(11):1303-1308 (1994).
10	(-)-Cercosporamide derivatives as novel antihyperglycemic agents. Bioorg Med Chem Lett. 2009 Feb 1;19(3):724-6.
11	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.
12	Synthesis of anilino-monoindolylmaleimides as potent and selective PKCbeta inhibitors. Bioorg Med Chem Lett. 2004 Oct 18;14(20):5171-4.
13	Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett. 1996 Aug 26;392(2):77-80.
14	(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.
15	How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
16	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.
17	Tannins as selective inhibitors of protein kinase C, Bioorg. Med. Chem. Lett. 2(3):239-244 (1992).
18	Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem. 1992 Jan;35(1):177-84.
19	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.