Congratulations, Teams Jonathan & Michael!

Specifically, we reveal that compounds marketed as selective HUWE1 inhibitors are, in fact, efficient substrates of their target ligase, thus competing with protein substrates for ubiquitination in vitro.

We establish cellular detection methods, confirming HUWE1 promotes — but does not exclusively drive —compound ubiquitination in cells. This opens avenues for harnessing the ubiquitin system to transform synthetic small molecules into novel chemical modalities within cells.