Targeted protein degradation offers a novel therapeutic approach, enabling the selective degradation of disease-associated proteins that are otherwise difficult to target. Currently established strategies, such as PROTACs, frequently suffer from off-target effects and poor pharmacokinetics. This study presents a potential alternative strategy that could leverage the ubiquitin-proteasome system to degrade non-canonical targets by delivering an evolved E3 ligase capable of recognizing novel, disease-associated substrates. Specifically, we set out to evolve the degron bound by SIAH to enable recognition of NLRP3, a protein implicated in various inflammatory and neurodegenerative diseases. The previously established Phage-Assisted Continuous Evolution (PACE) was chosen as the evolution method due to its success in reprogramming peptide-specific enzymes such as proteases. While the optimization of the selection system outlined here is still ongoing, we are confident that this alternative approach toward targeted protein degradation could address some of the major challenges of other drugs in this field.