Gö6976, a FLT3 kinase inhibitor, exerts potent cytotoxic activity against acute leukemia via inhibition of survivin and MCL-1.

Mutations of the FMS-like tyrosine kinase 3 (FLT3) have been reported in about a third of patients with acute myeloid leukemia (AML). The presence of FLT3 mutations confers a poor prognosis. Thus, pharmacological inhibitors of FLT3 are of therapeutic interest for AML. Gö6976 is an indolocarbazole with a similar structural backbone to staurosporine. In the present study, we demonstrated that Gö6976 displays a potent inhibitory activity against recombinant FLT3 using an in vitro kinase assay, with an IC50 value of 0.7nM. Gö6976 markedly inhibited the proliferation of human leukemia cells having FLT3-ITD such as MV4-11 and MOLM13. We also observed that Gö6976 showed minimal toxicity for human normal CD34(+) cells. Gö6976 suppressed the phosphorylation of FLT3 and downstream signaling molecules such as STAT3/5, Erk1/2, and Akt in MV4-11 and MOLM13 cells. Interestingly, induction of apoptosis by Gö6976 was associated with rapid and pronounced down-regulation of the anti-apoptotic protein survivin and MCL-1. Suppression of survivin protein expression by Gö6976 was due to the inhibition of transcription via the suppression of STAT3/5. On the other hand, Gö6976 induced proteasome-mediated degradation of MCL-1. Previously described FLT3 inhibitors such as PKC412 are bound by the human plasma protein, α1-acid glycoprotein, resulting in diminished inhibitory activity against FLT3. In contrast, we found that Gö6976 potently inhibited phosphorylation of FLT3 and exerted cytotoxicity in the presence of human serum. In conclusion, Gö6976 is a potent FLT3 inhibitor that displays a significant antiproliferative activity against leukemia cells with FLT3-ITD through the profound down-regulation of survivin and MCL-1.