Sotrastaurin (AEB071)

2 years -80 in solvent

Orally administrated

Sotrastaurin has finished Phase II clinical trial in patients with Kidney Transplantation.

Saline

Sotrastaurin (< 10uM) treatment effectively abrogated at low nanomolar concentration markers of early T-cell activation, such as interleukin-2 secretion and CD25 expression, in primary human and mouse T cells. Sotrastaurin (200 nM) inhibits the CD3/CD28 antibody- and alloantigen-induced T-cell proliferation responses in the absence of nonspecific antiproliferative effects. Sotrastaurin (<3 uM) markedly inhibits lymphocyte function-associated antigen-1-mediated T-cell adhesion. [1] Sotrastaurin(< 20 uM) selectively impair the proliferation of CD79 mutant ABC DLBCL cell lines, correlating with decreased NF-kappaB signaling avctivity. AEB071 at concentration of 5 uM induces G1 arrest and/or cell death in CD79 mutant cells. [2]

Protein Kinase Assays, Classical and novel PKC isotypes are assayed by scintillation proximity assay technology. In brief, the assay is performed in 20 mM Tris-HCl buffer, pH 7.4, and 0.1% bovine serum albumin by incubating 1.5 uM of the peptide substrate with 10 uM [33P]ATP, 10 mM Mg (NO3)2, 0.2 mM CaCl2, and PKC at a protein concentration varying from 25 to 400 ng/mL, and lipid vesicles containing 30 mol% phosphatidylserine, 5 mol% diacylglycerol (DAG), and 65 mol% phosphatidylcholine at a final lipid concentration of 0.5 uM. Incubation is performed for 60 min at room temperature. The reaction is stopped by adding 50 ul of a mixture containing 100 mM EDTA, 200 uM ATP, 0.1% Triton X-100, and 0.375 ug/well streptavidin-coated scintillation proximity assay beads in PBS without Ca2+ and Mg2+. Incorporated radioactivity is measured in a MicroBetaTrilux counter for 1 min.

Sotrastaurin (AEB071) is a potent and selective pan-PKC inhibitor, mostly for PKCθ with Ki of 0.22 nM in a cell-free assay; inactive to PKCζ. Phase 2.

Unlike former PKC inhibitors, Sotrastaurin does not enhance apoptosis of murine T-cell blasts in a model of activation-induced cell death.