EXEL-0862, a novel tyrosine kinase inhibitor, inhibits KIT activation and induces apoptosis in human mast cells bearing mutated codon 816 c-kit in vitro and ex vivo: Therapeutic implications

4039 Systemic mastocytosis is characterized by a clonal accumulation of mast cells in bone marrow and other tissues. The proto-oncogene c-kit , which encodes a transmembrane tyrosine kinase, is thought to play an important role in mastocytosis. Kinase inhibitors in clinical use, such as imatinib mesylate, failed to inhibit the growth of HMC1.2 cells bearing a codon 816 mutation of c-kit in laboratory testing. Consequently, there is a need for development of new effective therapeutic modalities. In this investigation, we determined the effect of exEL-0862, a novel tyrosine kinase inhibitor, on human mast cells. Two human mast cell lines, HMC1.1 carrying juxtamembrane domain mutation in codon 560 and HMC1.2 carrying both codon 560 mutation and tyrosine kinase mutation in codon 816 of c-kit , were used. We found that EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner. In MTS assay, EXEL-0862 decreased viability in both mast cell lines with a more potent inhibitory effect on HMC1.2 cells (IC50 was 510 nM in HMC1.1, and 350 nM in HMC1.2 cells, p ex vivo antineoplastic effect of EXEL-0862 on mast cells from bone marrow samples from patients with mastocytosis. Treatment with 0.1 to 1.0 μM EXEL-0862 for 7 days resulted in a significant reduction in the mast cell percentage determined by flow cytometry (n=3). Taken together, our results demonstrated EXEL-0862 to be a potent mutated KIT inhibitor, which warrants clinical investigation of this compound in systemic mastocytosis.