ONO-7475 is a potent and selective inhibitor of active novel Axl/Mer tyrosine kinase with IC50 values of 0.7nM and 1nM, respectively. It potently arrested growth and induced apoptosis in acute myeloid leukemia with internal tandem duplication mutation of FMS-like tyrosine kinase 3.
Anexelekto (AXL) is a receptor tyrosine kinase (RTK) of the TAM (Tyro3, AXL, and MER) family. Activation of AXL by growth arrest specific 6 (GAS6) induces diverse survival cascades. Recent studies have revealed that AXL regulates survival signaling in many cancers, including leukemia. ONO-7475 is an inhibitor with high specificity for AXL and MER tyrosine kinase with IC50 values of 0.7 nM and 1.0 nM, respectively. In MOLM13 and MV4;11 cells, ONO-7475 (10 nM; 48 h) significantly reduced cell viability by >50% and induced apoptosis. After 72 hours, 10 nM ONO-7475 nearly eliminated all viable MOLM13 cells with >70% of cells becoming apoptotic. MOLM13 cells in monoculture or in co-culture with MSC (mesenchymal stromal cells) were incubated for 72 hours with vehicle or ONO-7475. The drug potently induced apoptosis and nearly eliminated the AML cells in monoculture. While MSC protected the AML cells from the inhibitor, treatment with a higher dose of drug abrogated most of this effect (50 nM ONO-7475). Low dose ONO-7475 (5 nM) suppressed DNA synthesis in MOLM13 and MV4;11 cells by >2-fold. ONO-7475 potently induced G0/G1 arrest in both cell lines. MOLM13 and MV4;11 were incubated with varying doses of ONO-7475 for 24 hours, ONO-7475 potently suppressed both Cyclin B1 and CDK1 in both cell lines even at a low dose (10 nM). Moreover, AXL is known to induce ERK, and ERK is a positive regulator of MCL-1. ONO-7475 reduced ERK phosphorylation (~50% at 10 nM) and suppressed MCL-1 (>80% at 10 nM) in MOLM13 cells. In a human AML xenograft model, mice given feed with 0.004% ONO-7475 (0.004% is roughly 6 mg/kg daily consumption of drug) exhibited significantly longer median survival compared to mice given control feed. On Day 14, three out of five of the mice given food containing ONO-7475 exhibited reduced leukemic burden compared to the mice which were fed control food[1].
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