Acute Myeloid Leukemia (AML) is an aggressive form of leukemia with over 20,000 new cases reported in the year 2015 in the US alone, as estimated by the American Cancer Society. The disease is associated with a block in differentiation of hematopoietic progenitor cells resulting in uncontrolled proliferation and a malignant clonal disorder. Approximately one third of patients suffering from Acute Myeloid Leukemia harbor a FLT3 internal tandem duplication mutation (FLT3-ITD). When mutated, this receptor tyrosine kinase promotes pathways for proliferation and blocks apoptosis.<br/>Here, we tested the utility of ON150030, developed in our laboratory, as a novel therapeutic agent to treat AML. Structural studies suggest ON150030 binds to the active form of FLT3 (Type 1 inhibitor) so mutations such as D835X do not affect the inhibitory activity of the compound. In vitro kinase assays demonstrate that ON150030 potently inhibits Wildtype and FLT3-D835Y forms, while Quizartinib fails to inhibit FLT3-D835Y. Additionally, ON150030 demonstrated time and temperature dependent inhibition of FLT3, suggesting that the compound could be an irreversible inhibitor of FLT3. Biological studies reveal that ON150030 specifically inhibits the growth of MV4-11 cells harboring the FLT3-ITD mutation (GI50: 10nM). Mouse xenograft models were used to assess the drug’s effect in vivo. Animals treated with ON150030 exhibited dramatic regression of subcutaneous tumors compared to control.

Discovery of a novel kinase inhibitor ON 150030, a type 1 inhibitor for relapsed and refractory AML

255th National Meeting (2018)

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