Discovery and Rational Design of Pteridin-7(8<i>H</i>)‑one-Based Inhibitors Targeting FMS-like Tyrosine Kinase 3 (FLT3) and Its Mutants

FLT3 has been validated as a therapeutic target for the treatment of acute myeloid leukemia (AML). In this paper, we describe for the first time, pteridin-7­(8<i>H</i>)-one as a scaffold for potent FLT3 inhibitors derived from structural optimizations on irreversible EGFR inhibitors. The representative inhibitor (<b>31</b>) demonstrates single-digit nanomolar inhibition against FLT3 and subnanomolar <i>K</i>_D for drug-resistance FLT3 mutants. In profiling of the in vitro tumor cell lines, it shows good selectivity against AML cells harboring FLT3-ITD mutations over other leukemia and solid tumor cell lines. The mechanism of action study illustrates that pteridin-7­(8<i>H</i>)-one derivatives suppress the phosphorylation of FLT3 and its downstream pathways, thereby inducing G₀/G₁ cell cycle arrest and apoptosis in AML cells. In in vivo studies, <b>31</b> significantly suppresses the tumor growth in MV4–11 xenograft model. Overall, we provide a structurally distinct chemical scaffold with which to develop FLT3 mutants-selective inhibitors for AML treatment