Target Validation Information
Target ID T40276
Target Name Protein kinase C, beta type
Target Type
Clinical Trial
Drug Potency against Target RO-320432 Drug Info IC50 = 30.5 nM
3-(1H-Indol-3-yl)-4-phenylamino-pyrrole-2,5-dione Drug Info IC50 = 223 nM [527221]
[2,2':5',2'']Terthiophene-4-carbaldehyde Drug Info IC50 = 5000 nM [525575]
Sotrastaurin acetate Drug Info Ki = 0.64 nM [552850]
Ro-32-0557 Drug Info IC50 = 6.8 nM
RO-316233 Drug Info IC50 = 550 nM [528701]
[2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde Drug Info IC50 = 700 nM [525575]
PROSTRATIN Drug Info Ki = 12.5 nM [527606]
BALANOL Drug Info IC50 = 40 nM
LY-326449 Drug Info IC50 = 630 nM [534154]
[2,2':5',2'']Terthiophen-4-yl-methanol Drug Info IC50 = 3000 nM [525575]
Enzastaurin Drug Info IC50 = 30 nM [552971]
PUNICAFOLIN Drug Info IC50 = 4000 nM
Indolocarbazole analogue Drug Info IC50 = 3 nM [526234]
(-)-Cercosporamide Drug Info IC50 = 350 nM [529887]
LY-317644 Drug Info IC50 = 6400 nM
Action against Disease Model Enzastaurin Enzastaurin (LY317615.HCl) is an antiproliferative agent targeted specifically against PKC-|?? We have investigated the antit uMoral effects of Enzastaurin against h uMan cancercell lines (NSCLC, colon, and thyroid) and freshly explanted h uMan t uMor tissue. Inhibition of cell growth was observed for lung, colorectal, and thyroid cancer cell lines in a concentration dependent manner. Patient specimens exposed 1 h or 21 days to 1,400 nM Enzastaurin demonstrated inhibition rates of 24 and 32%, respectively. Marked inhibitory effects were observed in breast, thyroid, head/neck, non-small cell lung cancer, pancreatic cancer, and melanoma. In addition to its established antiangiogenic effects, Enzastaurin has direct antit uMor activity against established h uMan cancer cell lines and primary t uMor specimens. IC50 values of Enzastaurin (nM) for established non-small cell lung, colon, and thyroid cancer cell lines Calu1 3,600 Calu3 90 Calu6 4,050 NCI-H520 1,150, HCT-116 8,800, B-CPAP 12 [552684] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations In the current study, we have uncovered a role for protein kinase Cbeta (PKCbeta) in TG homeostasis by studying the consequences of a targeted disruption of this kinase. PKCbeta(-/-) mutant mice were considerably leaner and the size of white fat depots was markedly decreased compared with wild-type littermates. TG content in the liver and skeletal muscle of PKCbeta(-/-) micewas also significantly low. Interestingly, mutant animals were hyperphagic and exhibited higher food intake and reduced feed efficiency versus wild type. The protection from obesity involves elevatedoxygen cons uMption/energy expenditure and increased fatty acid oxidation in adipose tissue with concurrent increased mitochondria genesis, up-regulation of PGC-1alpha and UCP-2, and down-regulation of perilipin. The ability of PKCbeta deficiency to promote fat burning in adipocytes may suggest novel therapeutic strategies for obesity and obesity-related disorders
References
Ref 527221Bioorg Med Chem Lett. 2004 Oct 18;14(20):5171-4.Synthesis of anilino-monoindolylmaleimides as potent and selective PKCbeta inhibitors.
Ref 525575Bioorg 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 552850The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. J Clin Invest. 2008 Sep;118(9):3151-9. doi: 10.1172/JCI35636.
Ref 528701J Med Chem. 1992 Jan;35(1):177-84.Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides.
Ref 525575Bioorg 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 527606J 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 534154J 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 525575Bioorg 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 552971Small molecule inhibitors of PKCTheta as potential antiinflammatory therapeutics. Curr Top Med Chem. 2009;9(7):640-54.
Ref 552684Antitumor activity of enzastaurin (LY317615.HCl) against human cancer cell lines and freshly explanted tumors investigated in in-vitro [corrected] soft-agar cloning experiments. Invest New Drugs. 2007 Jun;25(3):205-10. Epub 2007 Mar 9.
Ref 526234Bioorg Med Chem Lett. 2002 Jan 21;12(2):147-50.Mixed lineage kinase activity of indolocarbazole analogues.
Ref 529887Bioorg Med Chem Lett. 2009 Feb 1;19(3):724-6. Epub 2008 Dec 11.(-)-Cercosporamide derivatives as novel antihyperglycemic agents.

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