Combining classical SAR with nanoscale direct-to-biology chemistry yields METTL1 inhibitors that kill AML cells by occupying the SAM pocket
- Conventional SAR was combined with a tandem nanoscale direct-to-biology workflow to develop inhibitors of the tRNA m7G methyltransferase METTL1/WDR4.
- Lead VK238 inhibited the enzyme at nanomolar concentrations with selectivity across methyltransferase and kinase panels, and lowered tRNA m7G levels in cells, triggering apoptosis in several AML lines.
- Biophysical assays, photoaffinity labeling and docking indicated the series binds in the SAM pocket of METTL1.
💡 Points Based on the abstract
D2B earns its keep here by compressing make-test cycles, but crude-mixture hits are notorious for false positives, so resynthesized, purified VK238 is what counts. METTL1 SAM-pocket binders risk cross-reactivity with other methyltransferases, so I'd want cellular target engagement and a rescue experiment with catalytically dead METTL1 to link AML killing to on-target inhibition.
Development of Potent METTL1 Inhibitors Using a Nanoscale Direct-To-Biology Strategy ↗