molecules of the month

The Genentech XIAP E3-ligase degrader, compound 10, has an interesting mechanism of action, triggering the degradation of its target (XIAP) by ubiquitylation of the small molecule. The molecule behaves as a lysine mimetic, accepting ubiquitin from the targeted E3 complex, promoting XIAP’s own degradation. As E3 ligases are often difficult to drug, this “K-tag” approach adds an interesting new concept to the toolbox, which may be easier to translate into drugs than heterobifunctional degraders which tend to be much larger and less synthetically accessible.