Binding Mode
The only available X-ray co-crystal structure of
midostaurin is in complex with DYRK1A (dual
specificity tyrosine phosphorylation regulated
kinase 1A)(Fig.1). Midostaurin is anchored to the
hinge with two hydrogen bonds: the lactam NH with
amide carbonyl of Glu239; and the lactam carbonyl
with amide NH of Leu241 (Fig.2).
Description
PKC-412 (120685-11-2) is a broad spectrum kinase inhibitor. Inhibited kinases include, but are not limited to; PKA, PKC, S6 Kinase, KDR, PKC, Akt, EGFR, VEGFR, PDGFR, c-kit, and FLT-3. Acute myeloid leukemia related mutant forms of FLT-3 are also inhibited both in vitro and in vivo. PKC-412 has been demonstrated to induce apoptosis and shows broad antiproliferative activity in various tumor cell lines. Cell Permeable
Uses
Midostaurin is used as a broad spectrum protein kinase inhibitor. Inhibits conventional PKC isoforms (α, β, γ), PDFRβ, VEGFR2, Syk, PKCη, Flk-1, Flt3, Cdk1/B, PKA, c-Kit, c-Fgr, c-Src, VEGFR1 and EGFR. Displays potent antitumor activity. Due to this act which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors. Midostaurin was shown to possess antiproliferative characteristics via inhibition of protein kinase C, kinase insert domain receptor, and c-kit.
Definition
ChEBI: An organic heterooctacyclic compound that is the N-benzoyl derivative of staurosporine.
General Description
Class: receptor tyrosine kinase;
Treatment: AML, SM;
Other name: PKC-412, CGP41251;
Elimination half-life = 20 h;
Protein binding > 99%
Biological Activity
Broad spectrum protein kinase inhibitor. Inhibits conventional PKC isoforms ( α , β , γ ), PDFR β , VEGFR2, Syk, PKCη, Flk-1, Flt3, Cdk1/B, PKA, c-Kit, c-Fgr, c-Src, VEGFR1 and EGFR. Displays potent antitumor activity.
target
Primary targets: FLT3, KIT
References
1) Odgerel et al. (2008) The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations; Oncogene, 27 3102
2) El Fitori et al. (2007) PKC 412 small-molecule tyrosine kinase inhibitor: single-compound therapy for pancreatic cancer; Cancer, 110 1457
3) Miyatake, et al. ( 2007) PKC412 (CGP41251) modulates the proliferation and lipopolysaccharide-induced inflammatory responses of RAW 264.macrophages; Biochem. Biophys. Res. Commun., 360 115
4) Bahlis et.al. (2005) N-Benzoylstaurosporine (PKC412) inhibits Akt kinase inducing apoptosis in multiple myeloma cells; Leuk. Lymphoma, 46 899
5) Fabbro et al., (2000) PKC-412 – a protein kinase inhibitor with a broad therapeutic potential; Anticancer Drug Des., 15 17
