title: Gö6976 is a potent inhibitor of the JAK 2 and FLT3 tyrosine kinases with significant activity in primary acute myeloid leukaemia cells.
abstract: 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.
authors.affiliation: Department of Haematology, Royal Free and University College London Medical School, London, UK.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Grandage
authors.forename: Tamara
authors.initials: T
authors.lastname: Everington
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
authors.forename: Asim
authors.initials: A
authors.lastname: Khwaja
mesh_terms: D000208:Acute Disease; D002227:Carbazoles / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D002227:Carbazoles; D016207:Cytokines; D004791:Enzyme Inhibitors; D007211:Indoles; D007376:Interleukin-2; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011493:Protein Kinase C; D014443:Tyrosine; D051941:fms-Like Tyrosine Kinase 3; C108603:TEL-JAK2 fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C081021:Go 6976; C497970:FLT3 protein, human; C507933:JAK3 protein, human