3-(1H-Indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione

Description

Sotrastaurin (AEB071) is a potent and selective pan-PKC inhibitor, most potent against PKCθ with Ki of 0.22 nM in a cell-free assay; no activity against PKCζ. 

Application

Sotrastaurin has been used in trials studying the basic science and treatment of Uveal Melanoma, Richter Syndrome, Prolymphocytic Leukemia, Recurrent Mantle Cell Lymphoma, and Recurrent Small Lymphocytic Lymphoma, among others.

Uses

Sotrastaurin is an protein kinase C inhibitor that modulates migration and superoxide anion production by human neutrophils in vitro.

Uses

A potent selective pan-PKC inhibitor and highly inhibits PKCθ with a Ki of 0.22 nM.

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

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