Gö6976 is a potent inhibitor of the JAK 2 and FLT3 tyrosine kinases with significant activity in primary acute myeloid leukaemia cells

Br J Haematol. 2006 Nov;135(3):303-16. doi: 10.1111/j.1365-2141.2006.06291.x. Epub 2006 Sep 4.


Aberrant activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling is implicated in a number of haematological malignancies and effective JAK inhibitors may be therapeutically useful. We found that Gö6976, an indolocarbazole inhibitor of the calcium-dependent isozymes of protein kinase C (PKC), inhibited interleukin 3/granulocyte-macrophage colony-stimulating factor-induced signalling, proliferation and survival whereas Gö6983, a broad spectrum PKC inhibitor, had no such effects. Gö6976 was found to be a direct and potent inhibitor of JAK2 in vitro. Gö6976 also inhibited signalling, survival and proliferation in cells expressing the leukaemia-associated TEL-JAK2 fusion protein and the myeloproliferative disorder (MPD)-associated JAK2 V617F mutant. In primary acute myeloid leukaemia (AML) cells, incubation with Gö6976 reduced constitutive STAT activity in all cases studied. In addition, Akt and mitogen-activated protein kinase phosphorylation were reduced in 4/5 FLT3-internal tandem duplication (ITD) positive AML cases and 7/13 FLT3-wild-type (WT) cases. Expression of FLT3-WT, ITD and D835Y in 32D cells showed that Gö6976 is also a potent inhibitor of WT and mutant FLT3. In AML cells, Gö6976 reduced the survival to 55 +/- 5% of control in FLT3-ITD cases and to 69 +/- 5% in FLT3-WT samples. These data may help identify clinically useful compounds based on the structure of Gö6976, which can be employed for the treatment of MPDs as well as AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Carbazoles / pharmacology*
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytokines / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / pharmacology*
  • Interleukin-2 / metabolism
  • Janus Kinase 2 / metabolism*
  • Janus Kinase 3 / metabolism
  • Leukemia, Myeloid / metabolism*
  • Neoplasm Proteins / metabolism*
  • Oncogene Proteins, Fusion / metabolism
  • Phosphorylation
  • Protein Kinase C / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Stem Cells / drug effects
  • Tyrosine / metabolism
  • fms-Like Tyrosine Kinase 3 / metabolism*


  • Carbazoles
  • Cytokines
  • Enzyme Inhibitors
  • Indoles
  • Interleukin-2
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • TEL-JAK2 fusion protein, human
  • Go 6976
  • Tyrosine
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • JAK3 protein, human
  • Janus Kinase 2
  • Janus Kinase 3
  • Protein Kinase C