Identification of the Benzoimidazole Compound as a Selective FLT3 Inhibitor by Cell-Based High-Throughput Screening of a Diversity Library

Internal
tandem duplication in the FLT3 receptor tyrosine kinase
(FLT3/ITD mutation) occurs in approximately 25% of acute myeloid leukemia
(AML) patients. To specifically target this driver mutation in AML,
we assessed and compared the cell-based cytotoxicity of a diversity
library (10,000 compounds) against the normal cell line BaF3 and the
isogenic leukemic cell line BaF3/ITD. A benzoimidazole scaffold-based
compound (HP1142) was identified as the most selective compound against
a series of murine and human leukemia cells with FLT3/ITD. Novel benzoimidazole
compounds were further designed to improve the aqueous solubility
of HP1142. The most potent compound, HP1328, demonstrated desirable
pharmaceutical and pharmacokinetic properties. Treatment with HP1328
significantly reduced the leukemia burden and prolonged the survival
of mice with FLT3/ITD leukemia. Our findings establish the specific
activity of the benzoimidazole compound against FLT3/ITD leukemia
and warrant further investigation in this subset of leukemia patients
with poor prognosis.