A dual inhibitor overcomes drug-resistant FLT3-ITD acute myeloid leukemia.

ABSTRACT: FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Multiple FLT3 inhibitors are in various stages of clinical evaluation. However, resistance to FLT3 inhibitors resulting from acquired point mutations in tyrosine kinase domain (TKD) have limited the sustained efficacy of treatments, and a "gatekeeper" mutation (F691L) is resistant to most available FLT3 inhibitors. Thus, new FLT3 inhibitors against both FLT3 internal tandem duplication (FLT3-ITD) and FLT3-TKD mutations (including F691L) are urgently sought. Herein, we identified KX2-391 as a dual FLT3 and tubulin inhibitor and investigated its efficacy and mechanisms in overcoming drug-resistant FLT3-ITD-TKD mutations in AML. KX2-391 exhibited potent

SUBMITTER: Wang P 

PROVIDER: S-EPMC8255005 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature