Target Information
Target General Information | Top | |||||
---|---|---|---|---|---|---|
Target ID |
T40276
(Former ID: TTDC00163)
|
|||||
Target Name |
Protein kinase C beta (PRKCB)
|
|||||
Synonyms |
Protein kinase C beta type; PRKCB1; PKCB; PKC-beta; PKC-B
|
|||||
Gene Name |
PRKCB
|
|||||
Target Type |
Clinical trial target
|
[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Diffuse large B-cell lymphoma [ICD-11: 2A81] | |||||
2 | Lymphoma [ICD-11: 2A80-2A86] | |||||
3 | Malignant haematopoietic neoplasm [ICD-11: 2B33] | |||||
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.
Click to Show/Hide
|
|||||
BioChemical Class |
Kinase
|
|||||
UniProt ID | ||||||
EC Number |
EC 2.7.11.13
|
|||||
Sequence |
MADPAAGPPPSEGEESTVRFARKGALRQKNVHEVKNHKFTARFFKQPTFCSHCTDFIWGF
GKQGFQCQVCCFVVHKRCHEFVTFSCPGADKGPASDDPRSKHKFKIHTYSSPTFCDHCGS LLYGLIHQGMKCDTCMMNVHKRCVMNVPSLCGTDHTERRGRIYIQAHIDRDVLIVLVRDA KNLVPMDPNGLSDPYVKLKLIPDPKSESKQKTKTIKCSLNPEWNETFRFQLKESDKDRRL SVEIWDWDLTSRNDFMGSLSFGISELQKASVDGWFKLLSQEEGEYFNVPVPPEGSEANEE LRQKFERAKISQGTKVPEEKTTNTVSKFDNNGNRDRMKLTDFNFLMVLGKGSFGKVMLSE RKGTDELYAVKILKKDVVIQDDDVECTMVEKRVLALPGKPPFLTQLHSCFQTMDRLYFVM EYVNGGDLMYHIQQVGRFKEPHAVFYAAEIAIGLFFLQSKGIIYRDLKLDNVMLDSEGHI KIADFGMCKENIWDGVTTKTFCGTPDYIAPEIIAYQPYGKSVDWWAFGVLLYEMLAGQAP FEGEDEDELFQSIMEHNVAYPKSMSKEAVAICKGLMTKHPGKRLGCGPEGERDIKEHAFF RYIDWEKLERKEIQPPYKPKARDKRDTSNFDKEFTRQPVELTPTDKLFIMNLDQNEFAGF SYTNPEFVINV Click to Show/Hide
|
|||||
3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
ADReCS ID | BADD_A00503 ; BADD_A05675 | |||||
HIT2.0 ID | T25H22 |
Drugs and Modes of Action | Top | |||||
---|---|---|---|---|---|---|
Clinical Trial Drug(s) | [+] 5 Clinical Trial Drugs | + | ||||
1 | Enzastaurin | Drug Info | Phase 3 | Non-hodgkin lymphoma | [1], [2], [3] | |
2 | RUBOXISTAURIN HYDROCHLORIDE | Drug Info | Phase 3 | Lymphoma | [4] | |
3 | LY333531 | Drug Info | Phase 2 | Solid tumour/cancer | [5] | |
4 | Sotrastaurin acetate | Drug Info | Phase 2 | Renal transplantation | [6] | |
5 | MS-553 | Drug Info | Phase 1 | Chronic lymphocytic leukaemia | [7] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | Linetastine | Drug Info | Discontinued in Phase 2 | Rhinitis | [8] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Modulator | [+] 2 Modulator drugs | + | ||||
1 | Enzastaurin | Drug Info | [1] | |||
2 | RUBOXISTAURIN HYDROCHLORIDE | Drug Info | [4] | |||
Inhibitor | [+] 30 Inhibitor drugs | + | ||||
1 | LY333531 | Drug Info | [9], [10], [11] | |||
2 | Sotrastaurin acetate | Drug Info | [6] | |||
3 | MS-553 | Drug Info | [7] | |||
4 | Linetastine | Drug Info | [12] | |||
5 | BALANOL | Drug Info | [13] | |||
6 | LY-317644 | Drug Info | [14] | |||
7 | RO-320432 | Drug Info | [15] | |||
8 | (-)-Cercosporamide | Drug Info | [16] | |||
9 | 2,3,3-Triphenyl-acrylonitrile | Drug Info | [17] | |||
10 | 2-(4-Hydroxy-phenyl)-3,3-diphenyl-acrylonitrile | Drug Info | [17] | |||
11 | 3,3-Bis-(4-hydroxy-phenyl)-2-phenyl-acrylonitrile | Drug Info | [17] | |||
12 | 3,3-Bis-(4-methoxy-phenyl)-2-phenyl-acrylonitrile | Drug Info | [17] | |||
13 | 3-(1H-Indol-3-yl)-4-phenylamino-pyrrole-2,5-dione | Drug Info | [18] | |||
14 | 3-(4-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile | Drug Info | [17] | |||
15 | 4-cycloheptyliden(4-hydroxyphenyl)methylphenol | Drug Info | [17] | |||
16 | 4-cyclohexyliden(4-hydroxyphenyl)methylphenol | Drug Info | [17] | |||
17 | 4-cyclopentyliden(4-hydroxyphenyl)methylphenol | Drug Info | [17] | |||
18 | 4-[1-(4-hydroxyphenyl)-3-methyl-1-butenyl]phenol | Drug Info | [17] | |||
19 | Go 6983 | Drug Info | [19] | |||
20 | K00248 | Drug Info | [18] | |||
21 | LY-326449 | Drug Info | [20] | |||
22 | O-Phosphoethanolamine | Drug Info | [21] | |||
23 | PROSTRATIN | Drug Info | [22] | |||
24 | PUNICAFOLIN | Drug Info | [23] | |||
25 | RO-316233 | Drug Info | [24] | |||
26 | Ro-32-0557 | Drug Info | [15] | |||
27 | TANNIN | Drug Info | [23] | |||
28 | [2,2':5',2'']Terthiophen-4-yl-methanol | Drug Info | [25] | |||
29 | [2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde | Drug Info | [25] | |||
30 | [2,2':5',2'']Terthiophene-4-carbaldehyde | Drug Info | [25] |
Chemical Structure based Activity Landscape of Target | Top |
---|---|
Drug Property Profile of Target | Top | |
---|---|---|
(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
|
||
(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
|
||
(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
|
||
"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Co-Targets | Top | |||||
---|---|---|---|---|---|---|
Co-Targets |
Target Poor or Non Binders | Top | |||||
---|---|---|---|---|---|---|
Target Poor or Non Binders |
Target Regulators | Top | |||||
---|---|---|---|---|---|---|
Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target-Related Models and Studies | Top | |||||
---|---|---|---|---|---|---|
Target Validation |
References | Top | |||||
---|---|---|---|---|---|---|
REF 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. | |||||
REF 2 | URL: 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: 5693). | |||||
REF 3 | Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127. | |||||
REF 4 | Ruboxistaurin: LY 333531. Drugs R D. 2007;8(3):193-9. | |||||
REF 5 | ClinicalTrials.gov (NCT00482976) Effect of LY333531 on Vascular and Neural Functions. U.S. National Institutes of Health. | |||||
REF 6 | Emerging drugs for psoriasis. Expert Opin Emerg Drugs. 2009 Mar;14(1):145-63. | |||||
REF 7 | ClinicalTrials.gov (NCT03492125) A Study Of The Selective PKC-beta Inhibitor MS- 553. U.S. National Institutes of Health. | |||||
REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002311) | |||||
REF 9 | 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. | |||||
REF 10 | Protein kinase C activation and its pharmacological inhibition in vascular disease. Vasc Med. 2000;5(3):173-85. | |||||
REF 11 | 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. | |||||
REF 12 | Potential new medical therapies for diabetic retinopathy: protein kinase C inhibitors. Am J Ophthalmol. 2002 May;133(5):693-8. | |||||
REF 13 | Evaluation of differential hypoxic cytotoxicity and electrochemical studies of nitro 5-deazaflavins, Bioorg. Med. Chem. Lett. 5(18):2155-2160 (1995). | |||||
REF 14 | Synthesis of bisindolylmaleimide macrocycles, Bioorg. Med. Chem. Lett. 5(18):2093-2096 (1995). | |||||
REF 15 | 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 16 | (-)-Cercosporamide derivatives as novel antihyperglycemic agents. Bioorg Med Chem Lett. 2009 Feb 1;19(3):724-6. | |||||
REF 17 | 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. | |||||
REF 18 | Synthesis of anilino-monoindolylmaleimides as potent and selective PKCbeta inhibitors. Bioorg Med Chem Lett. 2004 Oct 18;14(20):5171-4. | |||||
REF 19 | 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 20 | (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. | |||||
REF 21 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
REF 22 | 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. | |||||
REF 23 | Tannins as selective inhibitors of protein kinase C, Bioorg. Med. Chem. Lett. 2(3):239-244 (1992). | |||||
REF 24 | Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem. 1992 Jan;35(1):177-84. | |||||
REF 25 | 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. |
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.