生物活性

• 靶点	PKCθ Ki:0.22nM

• 描述Protein kinase C (PKC) is a serine/threonine protein kinase, which plays a crucial role in signaling transduction mechanisms in many cell types and tissues. Sotrastaurin (AEB071), as an immuno- suppressor, is a pan selective PKC inhibitor with Ki value of 0.95 nM, 0.64 nM, 2.1 nM, 3.2 nM, 1.8 nM and 0.22 nM for PKCα, PKCβ1, PKCδ, PKCε, PKCη and PKCθ (measured by scintillation proximity assay technology). Sotrastaurin suppresses T-cell activation, in a complementary and different manner to calcineurin inhibitor such as cyclosporine A. Sotrastaurin can effectively abrogate CD3/CD28 antibody and alloantigen-driven T-cell responses. Treatment with sotrastaurin at a concentration of 250 nM can markedly decrease proliferation responses induced by antibody- or phorbol ester treatment in mouse CD3 T cells. Both IL-2 and IFNγ levels were strongly inhibited by sotrastaurin (<1000 nM) in the transgenic TCR DO11.10 mouse CD4+ T cells after physiological stimulation with the antigenic OVA peptide. This inhibition on T cells may due to the suppression on the canonical NF-κB and NFAT transactivation pathway. Sotrastaurin strongly inhibited phorbol ester-induced adhesion responses of Jurkat cells with an IC50 value of 300 nM, in stark contrast with CsA treatment inactive up to 1 μM in this assay^[1]. The almost completed inhibition of Sotrastaurin on CD25 expression was achieved at 2h, with >60% inhibition remaining 6h after administration in the T lymphocytes activated by anti-CD28 antibody in combination with PMA, from Lewis rats treated with a single oral dose of sotrastaurin on 30 mg/kg^[2]. Oral administration of sotrastaurin on 30 mg/kg, b.i.d, showed immunosuppressive effect and led to pronounced prolongation survival in rats with heart allograft^[2]. Sotrastaurin is being developed as an immunosuppressive for organ transplantation. Up to now, several phase 2 studies on efficacy, safety and tolerability of sotrastaurin on transplantation have been completed (see https://clinicaltrials.gov/).
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  92.1	0.5 μM	Growth Inhibition Assay	3 h	enhances IR-induced reduction in cell viability	24595385
  92.1	0.5 μM	Growth Inhibition Assay	3 h	increases IR-induced cell cycle arrest	24595385
  92.1	0-5 μM	Growth Inhibition Assay	72 h	inhibits cell growth dose dependently	22653968

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• 动物研究
  剂量	Mice[3] (p.o.): 80 mg/kg; rat[2] (p.o.): 3 mg/kg - 10 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Rats[2] Dose 20 mg/kg (p.o.) 5 mg/kg (i.v.) Administration p.o. i.v. Cmax 623 ng/ml (p.o.) T1/2 3.2 h (i.v.) F 0.34 Tmax 0.5 h (p.o.) AUC 2209 ng/g·h (p.o.) 1629 ng/g·h (i.v.) CL 3070 ml/h/kg

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00410228	Healthy	Phase 1	Completed	-	Switzerland ... more >> Novartis Investigative Site Bern, Switzerland Collapse <<
  NCT00492869	Kidney Transplantation	Phase 1 Phase 2	Completed	-	-
  NCT00555789	Kidney Transplantation	Phase 2	Terminated	-	United States, California ... more >> Novartis Investigative Site San Francisco, California, United States, 94143-0780 United States, Wisconsin Novartis Investigative Site Madison, Wisconsin, United States, 53706 Canada Novartis Investigative Site Halifax, Canada, B3H 1V7 France Novartis Investigative Site Le Kremlin Bicetre, France, 94270 Novartis Investigative Site Nantes, France, 44035 Novartis Investigative Site Paris, France, 75015 Novartis Investigative Site Toulouse, France, 31403 Germany Novartis Investigative Site Berlin, Germany, 13353 Novartis Investigative Site Berlin, Germany Novartis Investigative Site Essen, Germany, 45122 Novartis Investigative Site Hannover, Germany, 30625 Novartis Investigative Site Heidelberg, Germany, 69120 Novartis Investigative Site Koeln, Germany Italy Novartis Investigative Site Bologna, Italy, 40138 Novartis Investigative Site Firenze, Italy, 50134 Novartis Investigative Site Padova, Italy, 35128 Spain Novartis Investigative Site Llobregat, Spain, 08907 Novartis Investigative Site Madrid, Spain, 28041 Novartis Investigative Site Malaga, Spain, 28041 Novartis Investigative Site Valencia, Spain, 46017 Switzerland Novartis Investigative Site Basel, Switzerland, 4031 Novartis Investigative Site Bern, Switzerland, 3010 Novartis Investigative Site Zürich, Switzerland, 8091 United Kingdom Novartis Investigative Site Cardiff, United Kingdom, CF14 4XW Novartis Investigative Site Glasgow, United Kingdom, G11 6NT Novartis Investigative Site London, United Kingdom Novartis Investigative Site Manchester, United Kingdom Collapse <<

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• 参考文献

• [1] Evenou JP, Wagner J, et al. The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation. J Pharmacol Exp Ther. 2009 Sep;330(3):792-801.

  [2] Weckbecker G, Pally C, et al. Effects of the novel protein kinase C inhibitor AEB071 (Sotrastaurin) on rat cardiac allograft survival using single agent treatment or combination therapy with cyclosporine, everolimus or FTY720. Transpl Int. 2010 May 1;23(5):543-52.

  [3] Naylor TL, Tang H, et al. Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B-cell lymphomas. Cancer Res. 2011 Apr 1;71(7):2643-53.