Identification of the Benzoimidazole Compound as a Selective FLT3 Inhibitor by Cell-Based High-Throughput Screening of a Diversity Library.
Tian TianShengyi ZhangBingling LuoFeng YinWenhua LuYiqing LiKezhi HuangQiao LiuPeng HuangG Garcia-ManeroShijun WenYumin HuPublished in: Journal of medicinal chemistry (2022)
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.
Keyphrases
- acute myeloid leukemia
- poor prognosis
- tyrosine kinase
- allogeneic hematopoietic stem cell transplantation
- end stage renal disease
- long non coding rna
- single cell
- epidermal growth factor receptor
- induced apoptosis
- endothelial cells
- chronic kidney disease
- ejection fraction
- cell therapy
- newly diagnosed
- stem cells
- type diabetes
- peritoneal dialysis
- cell proliferation
- risk factors
- adipose tissue
- bone marrow
- ionic liquid
- combination therapy
- insulin resistance