Structure-based design of pan-YTHDF m6A reader inhibitors with cellular activity in AML
- Structure-based design gave pan-YTHDF inhibitor 34, which spares the related YTHDC1 and YTHDC2 readers, backed by YTHDF2 co-crystal structures.
- Inhibitor 31 and its methylated inactive analogue 31b form a negative-control pair; thermal shift assays showed cellular target engagement for 34 and 31 but not 31b.
- Both actives slowed AML cell growth, and 31 raised TNFRSF1B transcript level and stability, sensitizing THP-1 cells to TNF-alpha toxicity.
💡 Points Based on the abstract
An active and methylated-inactive pair is exactly what a chemical probe should come with, and it makes the TNFRSF1B story more believable. Still, pan-YTHDF inhibition cannot separate paralog roles. A YTHDF2 knockout or binding-site mutant rescue would show whether the AML growth effect is truly on-target.