UC Irvine

Cellular control over protein stability is essential for homeostasis and adaptation. Proximity underlies the ability of cells to selectively degrade proteins and can be hijacked for therapeutics by targeted protein degradation (TPD). TPD therapeutics eliminate disease-causing proteins by inducing protein proximity with cellular degradation machinery. Since all proteins are eventually broken down, TPD has the potential to eliminate any protein within the proteome. The immense diversity within the human proteome is complemented by many routes and signals for protein degradation. However, most degraders rely on the same pathway for protein clearance, the ubiquitin-proteosome system, which limits the number of proteins we can currently target. Our lab has shown that natively, protein arginine methyltransferase (PRMT) enzymes can mark proteins for lysosomal degradation with a tag named the methylarginine degron. This thesis will discuss a small molecule platform that hijacks methylarginine degrons for TPD. We show that induced proximity with PRMT enzymes can eliminate targets on-command using Methylarginine TArgeting Chimeras (MrTACs). We devised a modular fusion tagging system to recruit PRMTs to protein targets using HaloTag and SNAP-tag fusion proteins. MrTACs could elicit upwards of >95% target degradation in a methylation- and lysosome-dependent manner across nativePRMT1 substrates and neo-substrates that are not typically methylated. Unlike the native methylarginine degron, which is only catalyzed by PRMT1, MrTAC degradation could be accomplished by recruiting any PRMT. We leveraged this generalizable activity to develop fully endogenous MrTACs by repurposing PRMT inhibitors into MrTAC degraders. Group-transfer chemistry enabled us to develop a scalable platform to transform orthosteric inhibitors into silent recruiters that eliminate the PRMT inhibitor upon enzyme binding. Group-transfer MrTACs could eliminate disease-causing proteins and showed an improved anti-cancer activity over existing inhibitors, demonstrating the therapeutic utility of MrTACs. Together, these data demonstrate the value of integrating native biology with TPD towards the goal of improving protein druggability.