The Novel Diketopiperazine Derivative, Compound 5-3, Selectively Inhibited the Proliferation of FLT3-ITD Mutant Acute Myeloid Leukemia (AML) Cells

The internal tandem duplication mutation of FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with high recurrence and mortality rates in acute myeloid leukemia (AML), making it a critical target for anti-AML therapies. Plinabulin is a diketopiperazines derivative that exhibits extensive anti-cancer potency by targeting β-tubulin. We designed and synthesized a novel FLT3 inhibitor, namely <b>5-3</b>, based on the structure of plinabulin and evaluated its effect on FLT3-ITD mutant AML cells. The results indicated that <b>5-3</b> potently and selectively inhibits the growth of mutant FLT3-expressingleukemia cells, and had no effect on FLT3 wide-type cancer cells, suggesting the antiproliferative activity of <b>5-3</b> depends highly on FLT3-ITD expression. Mechanically, <b>5-3</b> significantly suppressed the phosphorylation of FLT3 signaling pathway, including STAT5, Erk and Akt. Moreover, the efficiency of compound <b>5-3</b> is not associated with Plinabulin's typical target, β-tubulin. In conclusion, the study identified diketopiperazine derivative as a novel FLT3-ITD selective inhibitor. These results demonstrated that <b>5-3</b> might be a drug candidate for the treatment of FLT3-ITD-positive AML.