Discovery of Proteolysis-Targeting Chimera Molecules that Selectively Degrade the IRAK3 Pseudokinase

We
report the first disclosure of IRAK3 degraders in the scientific
literature. Taking advantage of an opportune byproduct obtained during
our efforts to identify IRAK4 inhibitors, we identified ready-to-use,
selective IRAK3 ligands in our compound collection with the required
properties for conversion into proteolysis-targeting chimera (PROTAC)
degraders. This work culminated with the discovery of PROTAC 23, which we demonstrated to be a potent and selective degrader
of IRAK3 after 16 h in THP1 cells. 23 induced proteasome-dependent
degradation of IRAK3 and required both CRBN and IRAK3 binding for
activity. We conclude that PROTAC 23 constitutes an excellent in vitro tool with which to interrogate the biology of IRAK3.