Pyridazine nicotinamides as a new FTO inhibitor chemotype for AML
- A 67-compound SAR campaign on pyridazine-containing nicotinamides gave E6 as the most active FTO inhibitor, with binding confirmed by MST, CETSA and DARTS.
- E6 was active against MOLM-13 cells, raised global m6A, upregulated ASB2 and RARA and lowered c-Myc.
- It showed acceptable CYP safety and PK and inhibited MOLM-13 xenograft growth.
💡 Points
Another FTO series, but the useful part is the new scaffold: FTO chemotypes are still thin, and most earlier ones lean on the same few motifs. Potency is modest, so I'd treat E6 as a starting point and look for selectivity over ALKBH5 and other AlkB family members before reading too much into the cell phenotype.