Uses
A potent selective pan-PKC inhibitor and highly inhibits PKCθ with a Ki of 0.22 nM.
Uses
Sotrastaurin is an protein kinase C inhibitor that modulates migration and superoxide anion production by human neutrophils in vitro.
Definition
ChEBI: A member of the class of maleimides that is maleimide which is substituted at position 3 by an indol-3-yl group and at position 4 by a quinazolin-4-yl group, which in turn is substituted at position 2 by a 4-methylpiperazin-1-yl group. It is a potent and s
lective inhibitor of protein kinase C and has been investigated as an immunosuppresant in renal transplant patients.
Biological Activity
aeb071 is an inhibitor of protein kinase c (pkc). the pkc inhibitor which can block the t-cell activation has the ability of immune suppression [1].the protein kinase c (pkc) isoforms is very important in cell signaling, proliferation, differentiation, migration, survival, and death. pkc family has many isoforms. among the pkc isoforms, pkc isoforms have basal effect on the t cells’ activation and other immune cell functions [2,3].abe071 is a potent inhibitor of novel and classical pkc isoforms. through the inhibition of pkc, aeb071 can depress the activation and proliferation of t-cell and decrease the production of cytokine.abe071 can also suppress the nk cell activity. ex vivo stimulation of lymphocytes from subjects exposed to single doses of aeb071 resulted in a dose-dependent inhibition of both lymphocyte proliferation and il2 mrna expressionaeb071 is an effective treatment strategy for the cure of autoimmune diseases. according to the psoriasis area severity index (pasi) score, after 2 weeks’ treatment with 300 mg bid aeb071, clinical severity of psoriasis was reduced up to 69% compared with baseline[2,3].
in vivo
The combination therapy results in a significantly enhanced reduction in tumor volume when compared to either Sotrastaurin (AEB071) or BYL719 alone (p=0.049 vs. BYL719 and p=0.022 vs. Sotrastaurin at day 26). There is even a greater effect when compared to vehicle control (p=0.016)[2]. Sotrastaurin (STN) treatment of liver donors and orthotopic liver transplantation (OLT) recipients (Gr.I) or of OLT recipients alone (Gr.II) prolongs animal survival, as 9 out of 10 rats in Gr. I, and 6 out of 6 rats in Gr.II survive >14 days. In contrast, only 4 out of 10 control OLT recipients remain alive at day 14 (p<0.01)[3].
IC 50
PKCθ: 0.22 nM (Ki); PKCβI: 0.64 nM (Ki); PKCα: 0.95 nM (Ki); PKCη: 1.8 nM (Ki); PKCδ: 2.1 nM (Ki); PKCε: 3.2 nM (Ki)
References
[1]. weckbecker g1, pally c, beerli 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
[2]. skvara h1, dawid m, kleyn e, wolff b, et al. the pkc inhibitor aeb071 may be a therapeutic option for psoriasis. j clin invest. 2008 sep;118(9):3151-9.
[3]. matz m1, weber u, mashreghi mf, et al. effects of the new immunosuppressive agent aeb071 on human immune cells. nephrol dial transplant. 2010 jul;25(7):2159-67
