Over the last few years, the targeted protein degradation field has developed at an astonishing rate. AstraZeneca has invested substantial resources into keeping up with the pace and as a result has acquired a deep collective knowledge of the unique challenges posed by this relatively new modality. We have come to learn that for PROTACs these include early mechanistic investigations such as characterizing degrader selectivity, determining target protein turnover rates and quantifying the target and requisite E3 ligases in selected models of efficacy and safety. In this workshop, members of the Chemical Biology and Proteomics department at AstraZeneca will review and discuss the impact of mass spectrometry based proteomics on the field of protein degraders and offer their perspectives on where the field of proteomics needs to develop in order to meet these challenges.

• Assessment of target protein turnover rate via proteomic methods : an essential early activity in the degrader drug discovery process
• Outlining proteomics strategies to assess E3 ligase (and POI) levels across efficacy and safety models to drive degradation selectivity
• Discussing global proteomics and genetic knockouts: powerful tools for degrader target identification and validation and for gaining insights into distal pathway effects to inform on degrader selectivity