Exploration of protein degradability enables fully endogenous MrTAC degraders.

Small molecules can induce protein degradation by hijacking natural degrons, but most degraders rely on the same proteasome-targeting degron. Motivated by the need for chemically exploitable degrons, this study leverages the lysosome-targeting methylarginine degron for the development of methylarginine-targeting chimeras (MrTACs). First, lysosomal-capture proteomics identify substrates naturally modified by methylarginine degrons. Next, a tag-based protein library is used for understanding the characteristics that affect degradation by MrTACs, which induces methylarginine degrons by recruiting protein arginine methyltransferases (PRMTs). MrTACs degrade proteins regardless of their native proteolytic route, including targets that have eluded classic degrader modalities, across multiple PRMTs. We leverage this for endogenous MrTACs that recruit PRMTs with repurposed inhibitors, which can be transformed into silent recruiters via group-transfer chemistry. MrTACs drive <95% target degradation across disease-linked proteins at nanomolar doses. Overall, this study integrates native and chemically induced degradation to establish a platform for fully endogenous, therapeutically viable degraders.