Reference Detail

Ref Type Journal Article
PMID (16956345)
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
Vol 135
Issue 3
Date 2006 Nov
URL
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Go6976 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).
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