Midostaurin

Midostaurin (PKC412; CGP 41251) is an orally active, reversible multi-targeted protein kinase inhibitor. Midostaurin inhibits PKCα/β/γ, Syk, Flk-1, Akt, PKA, c-Kit, c-Fgr, c-Src, FLT3, PDFRβ and VEGFR1/2 with IC₅₀s ranging from 22-500 nM^[1][2]. Midostaurin also upregulates endothelial nitric oxide synthase (eNOS) gene expression. Midostaurin shows powerful anticancer effects^[3]. IC50 & Target: IC50: 22 nM (cPKC-α), 30 nM (cPKC-β1), 31 nM (cPKC-β2), 24 nM (cPKC-γ), 330 nM (nPKC-δ), 160 nM (nPKC-η), 1.25 μM (nPKC-ε), 465 μM (aPKC-ζ), 38 nM (PPK), 570 nM (Protein kinase A), 95 nM (c-Syk), 86 nM (KDR), 912 nM (Flt-1), 1.90 μM (Myosin-light chain kinase)^[2] In Vitro: Midostaurin (PKC412) shows a broad antiproliferative activity against various tumor and normal cell lines in vitro, and is able to reverse the Pgp-mediated multidrug resistance of tumor cells in vitro. Exposure of cells to Midostaurin (PKC412) results in a dose-dependent increase in the G2/M phase of the cell cycle concomitant with increased polyploidy, apoptosis and enhanced sensitivity to ionizing radiation^[1]. Midostaurin (PKC412) induces substantial inhibition of KIT-, Lyn-, and STAT5 activity, but does not suppress Btk in HMC-1 cells and primary neoplastic mast cells^[3]. Midostaurin (PKC412) inhibits EN fusion tyrosine kinase in hematopoietic Ba/F3 cells. Midostaurin (PKC412) significantly inhibits EN phosphorylation in M0-91 and IMS-M2 cells in a dose-dependent manner^[4]. In Vivo: Midostaurin (PKC412) strongly inhibits retinal neovascularization as well as laser-induced choroidal neovascularization in murine models^[1]. Midostaurin (PKC412) (25 mg/kg, i.p.) protects mouse livers of the K18 Arg90Cys-overexpressing transgenic mice from Fas-induced apoptosis^[5].