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|Ref Type||Journal Article|
|Authors||Grandage VL, Everington T, Linch DC, Khwaja A|
|Title||Gö6976 is a potent inhibitor of the JAK 2 and FLT3 tyrosine kinases with significant activity in primary acute myeloid leukaemia cells.|
|Journal||British journal of haematology|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Go6976||FLT3 Inhibitor 50 JAK2 Inhibitor 17 PKC alpha Inhibitor 6 PKC beta Inhibitor 6||Go6976 binds and inhibits the calcium-dependent protein kinase C (PKC) isoforms, as well as Flt3, and mutant and wild-type Jak2, which may promote apoptosis and tumor regression (PMID: 8486620, PMID: 16956345).|
|Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|JAK2 V617F||acute myeloid leukemia||sensitive||Go6976||Preclinical||Actionable||In a preclinical study, Go 6976 inhibited proliferation of cultured acute myeloid leukemia cells expressing the JAK2 V617F mutation (PMID: 16956345).||16956345|