Bisindolyl maleimides

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Structural formula of GF 109203X

Bisindolylmaleimides are a group of organic chemical compounds . This is to indolsubstituierte maleimides . This can also be understood as pyrrole -2,5-dione. They are potent inhibitors of protein kinase C (PKC). The bisindolylmaleimide 1 used in numerous cell biochemical studies on cancer cells is 3- [1- (3-dimethylaminopropyl) indol-3-yl] -4- (1 H -indol-3-yl) -1 H -pyrrole-2,5 -dion and is also known as GF 109203X.

Occurrence

Bisindolylmaleimide 4, also Arcyriarubin A, the basic structure of the bisindolylmaleimide

The natural bisindolyl maleimide arcyriarubin A or bisindolyl maleimide 4 is the 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 bisindolyl derivatives.

Pharmacological importance

In vitro , the bisindiolyl maleimides show an inhibitory or apoptotic effect on numerous cancer cell lines . Bisindolylmaleimides block the various isoforms of protein kinase C with different potency . Bisindolyl derivative 11, and the related bisindolyl maleimide Ro 31-8220, block all isoforms of PKC (conventional, new and atypical PKCs). Bisindolylmaleimides have a 1000 times weaker effect on protein kinase A than the lead substance staurosporine . This results in the pharmacological importance of this group of substances. Bisindolylmaleimides, however, are less specific towards other kinases. For example, Arcyriarubin A , GF 109203X and Ro 318220 show an inhibiting effect on CHK2, GSK-3β and nucleoside incorporations. Another disadvantage is that, in addition to other bisindolyl maleimides Ro 31-8220, the negative regulation of PKC causes an amplification of the Akt (PKB) signaling pathway. It increases the proliferation of melanoma cells in vitro . The inhibition of GSK-3β and PKCβ1 and -β2 continues to interfere with the insulin signaling pathway.

Use in medicine

Enzastaurinum

Enzastaurin ( INN : Enzastaurinum ) is a bisindolyl maleimide developed by Eli Lilly for the treatment of solid tumors. It was in phase III clinical trials until 2013 . Eli Lilly stopped development in 21013 after enzastaurin showed no significant advantages over placebo in progression-free survival.

Ruboxistaurin , a bisindolyl maleimide also developed by Eli Lilly, was in a phase III study in diabetic macular edema . Approval for this indication has not yet been granted.

Individual evidence

  1. ↑ Steglich, W. (1989): Slime molds (Myxomycetes) as a source of new biologically active metabolites . In: Pure Appl. Chem. , 61 (3); 281-288; doi : 10.1351 / pac198961030281 ; PDF (free full text, English)
  2. ↑ Schmitt, WD. Expression and regulation of MAPK phosphatases in ovarian carcinomas , dissertation 2005, Medical Faculty of the Charité; University Medicine Berlin;
  3. ^ The Binding Database
  4. ↑ Davies, SP. et al. (2000): Specificity and mechanism of action of some commonly used protein kinase inhibitors . In: Biochem. J. 351 (Pt1); 95-105; PMID 10998351 ; PDF (free full text access)
  5. ↑ Fang, X. et al. (2002): Convergence of multiple signaling cascades at glycogen synthase kinase 3: Edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase C-dependent intracellular pathway . In: Mol. Cell. Biol. 22 (7); 2099-2110; PMID 11884598 ; PMC 133668 (free full text, PDF).
  6. ↑ Huang, M. et al. (2003): Inhibition of Nucleoside Transport by Protein Kinase Inhibitors . In: J. Pharmacol. Exp. Ther. 304 (2); 753-760; PMID 12538831 ; PDF (free full text access)
  7. ↑ Wen, HC. et al. (2003): Negative regulation of phosphatidylinositol 3-kinase and Akt signaling pathway by PKC . In: Cell Signal. 15 (1); 37-45; PMID 12401518 ; doi : 10.1016 / S0898-6568 (02) 00047-5
  8. ↑ Kasagakis, K. et al. (2004): Proliferation of human melanoma cells is under tight control of protein kinase C alpha . In: J. Cell. Phys. 199 (3); 381-387; PMID 15095285 ; doi : 10.1002 / jcp.10434
  9. ↑ Hers, I. et al. (1999): The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31-8220) are potent inhibitors of glycogen synthase kinase-3 activity . In: FEBS Lett . 460 (3); 433-436; PMID 10556511 ;
  10. ↑ International Nonproprietary Names for Pharmaceutical Substances (INN) (PDF; 2.0 MB) WHO Drug Information, Vol. 18, No. 1, 2004
  11. ↑ Lilly Halts Development of Lymphoma Drug After Phase III Failure - GEN News Highlights - GEN. In: genengnews.com. May 10, 2013, accessed May 13, 2016 .
  12. ↑ Arxxant (ruboxistaurin mesylate) FDA Approval Status. In: drugs.com. Retrieved May 13, 2016 .

literature

  • I. Hers et al. : The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31-8220) are potent inhibitors of glycogen synthase kinase-3 activity. In: FEBS Lett 460, 1999, pp. 433-436. PMID 10556511
  • D. Verdelli et al. : Molecular targeting of the PKC-beta inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression. In: Hematol Oncol 2008; PMID 18759374
  • AC Spalding et al. : Enzastaurin, an inhibitor of PKCbeta, Enhances Antiangiogenic Effects and Cytotoxicity of Radiation against Endothelial Cells. In: Transl Oncol 1, 2008, pp. 195-201. PMID 19043530 ; PMC 2582168 (free full text)
  • LA Sorbera et al. : Enzastaurin hydrochloride. In: Drugs Fut 32, 2007, p. 297. doi : 10.1358 / dof.2007.032.04.1095514