ABSTRACT Receptor-interacting Protein Kinases 1 and 3 (RIPK1 and RIPK3) along with Mixed Lineage Kinase Domain- like (MLKL) pseudokinase are well-established players in a regulated necrotic cell death process, known as necroptosis. Activity of these proteins has been implicated in many disease states, including immunologic and inflammatory conditions. However, RIPK1 and RIPK3 scaffold functions that are distinct from their catalytic activities are much less explored. In addition, “kinase-domain” binding MLKL ligands developed thus far lacked uniform functional activities, suggesting need for a new strategy targeting this critical executioner of necroptosis. Consequently, molecular probes capable of selective degradation of these proteins will enable further progress in understanding necroptosis by elucidation of scaffold functions for these proteins. This work will also provide guidance for new therapeutic paradigms. To assess this hypothesis, proteolysis targeting chimeras (PROTACs) of RIPK3 and MLKL (Aim 1) will be generated leveraging previously identified ligands. These probes will be assessed for their ability to induce cellular degradation of RIPK3 and MLKL and, consequentially, to provide protection against pathologic necroptosis. Independently, probes that induce co- degradation of RIPK1 and Inhibitor of Apoptosis Proteins (IAPs) (Aim 2) will be developed, based on identification of new starting points for such molecules in our preliminary data. These co-degrader molecules will provide new options for inducing cell death in necroptosis-resistant cancer and activated myeloid cells. Overall, this project will provide critical data revealing the feasibility of targeting RIPK1, RIPK3 kinases and the pseudokinase MLKL for degradation as a new approach to understanding their kinase-independent functions that can also be leveraged in innovative therapeutic directions.