Editorial Volume 13, Issue 15 pp 19080—19082

Figure 1. Evolutional landmarks in FTO inhibitor discovery. Rhein, the first FTO inhibitor identified in 2012, did not impair viability in BE(2)-C neuroblastoma cells at a dose of 20 μM. MO-I-500, an inhibitor discovered in 2014, was found to inhibit survival of SUM149 breast cancer cells in glutamine (Gln)-free medium with an IC₅₀ of 20 μM, but had little effect on cells cultured in complete medium. Meclofenamic acid (MA) and its analogs were reported to be highly selective inhibitors of FTO. However, more than 90% of the Hela cells treated with 120 μM MA2 (an MA analog) remained viable. Fluorescein and its derivatives could simultaneously inhibit and label FTO and were therefore considered "bifunctional". At a concentration of up to 150 μM, fluorescein derivatives FL6 and FL8 did not display inhibitory effects on Hela cells with > 95% viable cells. In 2019, guided by the structural complex of FTO/MA, FB23 and FB23-2 were designed and optimized as two more potent FTO inhibitors. But the IC₅₀ for both inhibitors in acute myeloid leukemia (AML) were still in the micromolar range (23.6 – 44.8 μM for FB23 and 0.8 – 16 μM for the optimized FB23-2). In contrast, the most recently discovered small molecule FTO inhibitors, CS1 and CS2, have much lower IC₅₀ values in AML and solid tumors, especially in cancer cells that highly express FTO (in the low nanomolar range). CS1 and CS2 exert their anti-tumor activity by suppressing the FTO-mediated upregulation of MYC/CEBPA as well as LILRB4, thereby attenuating cancer stem cell (CSC) self-renewal and overcoming tumor immune evasion.