Discovery of Novel Pyridazine-Containing Nicotinamide Derivatives as Potent FTO Inhibitors for Acute Myeloid Leukemia
- J Med Chem. 2026 Oct 22;69(20):24420-24443. doi: 10.1021/acs.jmedchem.6c01981.
- 1. School of Pharmacy, Anhui Medical University, Hefei230032, P. R. China.
- 2. Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei230032, P. R. China.
- 3. Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei230601, P. R. China.
- 4. School of Life and Health Sciences, Environment Engineering, Hefei University, Hefei230601, P. R. China.
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.