Acute leukemia is a kind of cancer diseases, severely affects people’s life. Acute myeloid leukemia (AML) is a malignant neoplasia. They fail to differentiate into functional blood cells, and continue proliferation. As a result, myeloblasts accumulate in the bone marrow. FLT3 (FMS-like tyrosine kinase 3) mutation plays an important role in the development of AML. Therefore, it is necessary to find out more FLT3 inhibitor for acute leukemia research. Recently, researchers find out a significant FLT3 inhibitor, BSc5371. More experiments are as follows.
To begin with, Dennis Bensinger, et al characterizes 128 compounds. They screen the products, and detect the binding potency. To their delight, they discover compound 4b (BSc5371) as a potent and irreversible FLT3 inhibitor. BSc5371 exhibits Kds of 0.83 nM, 1.3 nM, 1.5 nM and 5.8 nM for mutant LT3(ITD, D835V), LT3(D835H), LT3(ITD, F691L) and FLT3-ITD. It also has a Kd of 2.3 nM for wild type FLT3wt.
Next, researchers carry out the cellular assays. They use MV4-11 cells as the subject. The cells are FLT3(ITD) positive, and sensitive to BSc5371. Furthermore, BSc5371 is also cytotoxic to Jurkat cells. These cells are FLT3wt THP1, NOMO1, U937 and FLT3-negative. In MV4-11 cells, BSc5371 displays an IC50 of 7.8 nM.
Meanwhile, reporters compare the potency of BSc5371 with that of structure-related compounds, such as 4a and 4c. BSc5371 exhibits more cytotoxicity to MOLM-14 cells than 4a. However, 4c is ineffective in the cells. BSc5371 also decreases pFLT3 and pSTAT5 levels in MOLM-14 cells.
In summary, BSc5371 is a potent and irreversible FLT3 inhibitor, with significant effect on acute myeloid leukemia. Researcher need to do more experiments to find out the potential of BSc5371 against acute leukemia.
Reference:
1. Bensinger D, et al. J Med Chem. 2019 Mar 14;62(5):2428-2446.