Bisindolylmaleimide

Bisindolylmaleimide are a group of organic chemical compounds. It involves indolsubstituierte maleimides. This can be as pyrrol-2 ,5- dione interpret. Are potent inhibitors of protein kinase C (PKC). The Bisindolylmalimid used in many cellular biochemical studies of cancer cells 1, 3 - [ 1 - (3 -dimethylaminopropyl) indol- 3-yl] -4 - ( 1H-indol- 3-yl )-1H -pyrrole-2 ,5-dione and is also referred to as GF 109203X.

Occurrence

The natural Bisindolylmaleimide Arcyriarubin A or bisindolylmaleimide 4 is unsubstituted bis [ 3,4 - ( 1H -indol- 3-yl )-1H -pyrrole-2 ,5 -dione from the Myxomycetes ( slime molds ) Arcyria major or Arcyria denudata. Myxomycetes produce a number of other Bisindolylderivate.

Pharmacological significance

In vitro, the Bisindiolylmaleimide show in numerous cancer cell lines, an inhibitory or apoptotic effect. Bisindolylmaleimide block with varying potency, the different isoforms of protein kinase C. Bisindolylderivat 11, and the bisindolylmaleimide Ro 31-8220 with this related, block all isoforms of PKC (conventional, new and atypical PKCs ). Bisindolylmaleimide act on protein kinase A is about 1000 times weaker than the lead compound staurosporine. This results in the pharmacological importance of this group of substances. However Bisindolylmaleimide are less specific over other kinases. To view Arcyriarubin A, GF 109203X and Ro 318220, for example, inhibitory effect on CHK2, GSK- 3β and Nukleosidinkorporationen. Another disadvantage is that in addition to other Bisindolylmaleimides Ro 31-8220 by the negative regulation of PKC a gain of Akt ( PKB) signaling pathway is caused. It enhanced the in vitro proliferation of melanoma cells. Through the inhibition of GSK- 3β and the PKCβ1 and β2 further carried out an intervention in the insulin - signaling pathway.

Use in medicine

Enzastaurin (INN: Enzastaurinum ) is a protocol developed by Eli Lilly Bisindolylmaleimide for the treatment of solid tumors. It is currently (as of January 2009) in the phase III clinical trials. Admission is about the orphan status - presumably for glioblastomas - done. Ruboxistaurin, which was also developed by Eli Lilly bisindolylmaleimide, is currently among other things, in a Phase - III - study in diabetic macular edema.