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/).

• 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