The Indolocarbazole Derivative Go6976 Suppresses The Growth Of Leukemia Cells With Flt3 Mutations

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in hematopoietic progenitor cell development. Mutations of FLT3 have been reported in about a third of patients with acute myeloid leukemia (AML), and inhibitors of FLT3 are of clinical interest. Go6976 is an indolocarbazole inhibitor of the calcium-dependent isozymes of protein kinase C (PKC). In the present study, we demonstrated that Go6976 possesses a potent inhibitory activity against recombinant FLT3 using in vitro kinase assay. We also showed that Go6976 is a potent inhibitor of Aurora-B kinase. Go6976 significantly inhibited proliferation of leukemia MV4-11 cells having FLT3-internal tandem duplication (ITD). Cell growth inhibition by Go6976 occurred in parallel with the drug inhibiting FLT3 and its downstream signal pathways such as extracellular signal-regulated kinase1/2, STAT-5 and p38. The FLT3-independent myeloid leukemia HL-60 and U937 showed strong resistance to Go6976 treatment. Induction of massive apoptosis were observed upon treatment with Go6976 in MV4-11 cells associated with significant down-regulation with Survivin and Mcl-1 protein. Interestingly, Go6976 treatment also inhibited Survivin phosphorylation on Thr34, which is critical for its anti-apoptotic activity. This inhibition of Survivin phosphorylation occurred due to the direct suppression of Aurora-B by Go6976 treatment. These data indicate that Go6976 may have a unique therapeutic potential for patients with FLT3-driven leukemias. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1806. doi:1538-7445.AM2012-1806