Abstract
FLT3 has been identified as a valid target for the treatment of acute myeloid leukemia (AML), and some FLT3 inhibitors have shown very good efficacy in treating AML in clinical trials. Nevertheless, recent studies indicated that relapse and drug resistance are still difficult to avoid, and leukemia stem cells (LSCs) are considered one of the most important contributors. Here, we report the characterization of SKLB-677, a new FLT3 inhibitor developed by us recently. SKLB-677 exhibits low nanomolar potency in biochemical and cellular assays. It is efficacious in animal models at doses as low as 1mg/kg when administrated orally once daily. In particular, SKLB-677 but not first-generation and second-generation FLT3 inhibitors in clinical trials has the ability to inhibit Wnt/β-catenin signaling; Wnt/β-catenin signaling is required for the development of LSCs, but not necessary for the development of adult hematopoietic stem cells (HSCs). This compound indeed showed considerable suppression effects on leukemia stem-like cells in in vitro functional assays, but had no influence on normal HSCs. Collectively, SKLB-677 is an interesting lead compound for the treatment of AML, and deserves further investigations.
Highlights
All of these results suggest that targeting the Wnt/β -catenin pathway may represent a new therapeutic strategy to eliminate leukemia stem cells (LSCs) and prevent Acute myeloid leukemia (AML) relapse and drug resistance[25,26]
The results showed that SKLB-677 (S (100 nM) = ~0.127) had poorer selectivity than the highly specific FMS-like tyrosine kinase 3 (FLT3) inhibitor AC200 (S (100 nM) = 0.028)[18], and comparable selectivity with the FDA-approved kinase inhibitors sunitinib (S (100 nM) = 0 .19) and dasatinib (S (100 nM) = 0 .159), but better selectivity than CEP-701 (S (100 nM) = 0.46)[18]
Negligible activity was observed against the remaining 16 human cancer cell lines. These results indicate that SKLB-677 is more sensitive to AML cells harboring an FLT3-internal tandem duplications (ITD) mutation than to other leukemia and solid tumor cell lines tested
Summary
SKLB-677 is one of the best compounds, which showed higher potencies in inhibiting FLT3 activation and Wnt/β -catenin signaling, and had better pharmacokinetic properties. SKLB-677 displayed very weak or no activity at a concentration of 10 μ M for other selected kinases, such as CDK2, BTK, DCLK1, ERBB2, MAST1, PAK4, PLK2, ROCK1, and TGFBR1. SKLB-677 potently inhibited the viability of FLT3-driven AML cell lines, MV4-11 and Molm-13, with IC50 values of 0.079 nM and 0.116 nM, respectively (Table 2 and Fig. 1d). It exhibited weak inhibitory activity against several other cell lines, including KG-1, HL-60, Jurkat, Ramos, Raji, Karpas-299, SU-DHL-6, PC-9, A549, H358, HepG2, and HeLa cells PC-9 H1975 H441 A549 H358 Miapaca-2 PANC-1 HepG2 SMMC7721 BEL7402 PLC/PRF/5 HeLa SW620
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