The novel δ,γ-biscarboline derivative T2 suppresses erythroleukemia through inhibition of AKR1B1 in the fructose metabolic reprogramming.

Fructose metabolic programming in cancer has been built to maintain malignant characteristics. Erythroleukemia is a subtype of acute myeloid leukemia with poor prognosis and therapeutic outcome. Herein, δ,γ-biscarboline derivatives were synthesized as novel bis-indolylpyridine compounds, containing N-alkylated pyridine. The δ,γ-biscarboline derivatives were screened and six new compounds were found exhibiting significant anti-leukemia activities. Among these derivatives, compound T2 displayed strong anti-leukemia activity in culture and in animal model of erythroleukemia, exhibiting negligible cytotoxicity. In molecular docking, T2 with high efficiency bound to the aldose reductase AKR1B1 in the fructose metabolism, resulting in downregulation of this protein that was further confirmed by CETSA and SRP analyses. While the inhibition rate with T2 increased in erythroleukemic cells overexpressing AKR1B1, substitution of amino acid residues (Lsy21 or Val47 to Ala) within this protein resulted in restoring the growth inhibition. The well-known AKR1B1 inhibitor epalrestat was found to target this protein through binding to the same domain, but generated hydrogen bonds with the different amino acid residues (Tyr48 and His110). Growth inhibition was decreased in the T2 and epalrestat co-treated group. Thus, T2 represents a novel and potent AKR1B1 inhibitor to suppress leukemia cell growth. Based on the structure of T2, a series of new analogous structures were synthesized, displaying diverse inhibitory activities to AKR1B1. Meanwhile, AKR1B1-overexpress in the erythroleukemia cells was found to activate the oncogene FLI1 which mediated malignant progression. T2 also downregulated FLI1 through inhibition of AKR1B1, which was in part responsible for its anti-erythroleukemia activities. Overall, this study is identified a novel compound that suppresses erythroleukemia through inhibition of AKR1B1 in the fructose metabolism reprogramming.