Target Validation Information
Target ID T00895
Target Name Protein kinase C, epsilon type
Target Type
Clinical Trial
Drug Potency against Target LY-326449 Drug Info IC50 = 630 nM [534154]
RO-316233 Drug Info IC50 = 550 nM [528701]
Indolocarbazole analogue Drug Info IC50 = 3 nM [526234]
[2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde Drug Info IC50 = 700 nM [525575]
Ro-32-0557 Drug Info IC50 = 48 nM
[2,2':5',2'']Terthiophene-4-carbaldehyde Drug Info IC50 = 5000 nM [525575]
LY-317644 Drug Info IC50 = 6400 nM
[2,2':5',2'']Terthiophen-4-yl-methanol Drug Info IC50 = 3000 nM [525575]
RO-320432 Drug Info IC50 = 105 nM
The Effect of Target Knockout, Knockdown or Genetic Variations PKC-epsilon(-/-) deficient knockout mice were generated and then killed after 6, 16, and 26 wk of life. Kidney/body weight ratio did not show any significant group difference compared with appropriate wild-type controls. Urinary alb uMin/creatinine ratio remained normal in wild-type mice, whereas PKC-epsilon(-/-) mice after 6 and 16 wk showed elevated alb uMinuria. Masson-Goldner staining revealed that tubulointerstitial fibrosis and mesangial expansion were significantly increased in PKC-epsilon(-/-) mice. However, this profibrotic phenotype was not observed in other organs, such as liver and lung. Immunohistochemistry of the kidneys from PKC-epsilon(-/-) mice showed increased renal fibronectin and collagen IV expression that was further aggravated in the streptozotocin-induced diabetic stress model. Furthermore, TGF-beta(1), phospho-Smad2, and phospho-p38 mitogen-activate protein kinase expression was increased in PKC-epsilon(-/-) mice, suggesting a regulatory role of PKC-epsilon in TGF-beta(1) and its signaling pathway in the kidney. These results indicate that deletion of PKC-epsilon mediates renal fibrosis and that TGF-beta1 and its signaling pathway might be involved. Furthermore, these data suggest that activation of PKC-epsilon in the diabetic state may rather represent a protective response to injury than be a mediator of renal injury. [534154]
References
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 528701J Med Chem. 1992 Jan;35(1):177-84.Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides.
Ref 526234Bioorg Med Chem Lett. 2002 Jan 21;12(2):147-50.Mixed lineage kinase activity of indolocarbazole analogues.
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 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 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.

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