Discovery of Novel Pyridazine-Containing Nicotinamide Derivatives as Potent FTO Inhibitors for Acute Myeloid Leukemia.

FTO has been recognized as a promising therapeutic target for acute myeloid leukemia (AML). However, the development of FTO inhibitors with anti-leukemia effects was still limited. Here, based on reasonable design and SAR, a total of 67 compounds were synthesized, among which compound E6 exhibited the strongest activity (FTO IC50 = 5.3 μM, KD = 3.25 μM). MST, CETSA, and DARTS detection confirmed its binding to FTO target. In addition, compound E6 exhibited good activity against MOLM-13 cells and induced it apoptosis. Mechanistic studies shown that compound E6 increased global m6A levels in AML cells, upregulated the FTO downstream targets ASB2 and RARA, and suppressed c-Myc expression. Importantly, compound E6 exhibited acceptable CYP safety and pharmacokinetic properties, significantly inhibited the growth of MOLM-13 xenograft tumors. These results provided novel chemical scaffold for discovery of FTO inhibitor against leukemia.