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]
• Related Disease:
  Diffuse large B-cell lymphoma [ICD-11: 2A81]
  Lymphoma [ICD-11: 2A80-2A86]
  Malignant haematopoietic neoplasm [ICD-11: 2B33]
• BioChemical Class: Kinase
• UniProt ID: KPCB_HUMAN
• TTD ID: T40276
• 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

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], [4], [5]
Sotrastaurin acetate	DME53YS	Renal transplantation	NE84	Phase 2	[6]
MS-553	DM7ER9J	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[7]

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	[8]
BALANOL	DMDLN9E	N. A.	N. A.	Terminated	[9]
LY-317644	DMM20PI	N. A.	N. A.	Terminated	[10]
RO-320432	DMFZ1YW	N. A.	N. A.	Terminated	[11]

23 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(-)-Cercosporamide	DMJ249P	Discovery agent	N.A.	Investigative	[12]
2,3,3-Triphenyl-acrylonitrile	DM7H34U	Discovery agent	N.A.	Investigative	[13]
2-(4-Hydroxy-phenyl)-3,3-diphenyl-acrylonitrile	DMNGW1A	Discovery agent	N.A.	Investigative	[13]
3,3-Bis-(4-hydroxy-phenyl)-2-phenyl-acrylonitrile	DMO51QG	Discovery agent	N.A.	Investigative	[13]
3,3-Bis-(4-methoxy-phenyl)-2-phenyl-acrylonitrile	DMZPYN2	Discovery agent	N.A.	Investigative	[13]
3-(1H-Indol-3-yl)-4-phenylamino-pyrrole-2,5-dione	DMP0RYB	Discovery agent	N.A.	Investigative	[14]
3-(4-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile	DME5238	Discovery agent	N.A.	Investigative	[13]
4-cycloheptyliden(4-hydroxyphenyl)methylphenol	DM4LIUC	Discovery agent	N.A.	Investigative	[13]
4-cyclohexyliden(4-hydroxyphenyl)methylphenol	DM8BLK2	Discovery agent	N.A.	Investigative	[13]
4-cyclopentyliden(4-hydroxyphenyl)methylphenol	DM7LN53	Discovery agent	N.A.	Investigative	[13]
4-[1-(4-hydroxyphenyl)-3-methyl-1-butenyl]phenol	DM8IYG1	Discovery agent	N.A.	Investigative	[13]
Go 6983	DMKVTZN	Discovery agent	N.A.	Investigative	[15]
K00248	DMWZJG6	Discovery agent	N.A.	Investigative	[14]
LY-326449	DMN53M4	Discovery agent	N.A.	Investigative	[16]
O-Phosphoethanolamine	DM3O9YW	N. A.	N. A.	Investigative	[17]
PROSTRATIN	DM1HMJ5	Human immunodeficiency virus infection	1C62	Investigative	[18]
PUNICAFOLIN	DM7CWQY	Discovery agent	N.A.	Investigative	[19]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[20]
Ro-32-0557	DMPVKEA	Discovery agent	N.A.	Investigative	[11]
TANNIN	DMTFHRI	Discovery agent	N.A.	Investigative	[19]
[2,2':5',2'']Terthiophen-4-yl-methanol	DMRQC1F	Discovery agent	N.A.	Investigative	[21]
[2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde	DMWDNLI	Discovery agent	N.A.	Investigative	[21]
[2,2':5',2'']Terthiophene-4-carbaldehyde	DM2S5EJ	Discovery agent	N.A.	Investigative	[21]

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.
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• [5] Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J Clin Invest. 1997 Jul 1;100(1):115-26.
• [6] Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63.
• [7] ClinicalTrials.gov (NCT03492125) A Study Of The Selective PKC-beta Inhibitor MS- 553. U.S. National Institutes of Health.
• [8] Potential new medical therapies for diabetic retinopathy: protein kinase C inhibitors. Am J Ophthalmol. 2002 May;133(5):693-8.
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• [12] (-)-Cercosporamide derivatives as novel antihyperglycemic agents. Bioorg Med Chem Lett. 2009 Feb 1;19(3):724-6.
• [13] 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.
• [14] Synthesis of anilino-monoindolylmaleimides as potent and selective PKCbeta inhibitors. Bioorg Med Chem Lett. 2004 Oct 18;14(20):5171-4.
• [15] Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett. 1996 Aug 26;392(2):77-80.
• [16] (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.
• [17] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [18] 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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• [20] Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem. 1992 Jan;35(1):177-84.
• [21] 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.