Molecular glues offer an incredible opportunity to expand the druggable genome. However, the number of proteins that can be degraded using this modality remains limited. This is in part a consequence of the limited number of E3 ligases that have been successfully exploited by glues. Structure function studies on the thalidomide analogs provide a paradigm for glue characterization and expansion for broader coverage of the proteome. The canonical cereblon system is a multi-step, sequential process leading to degradation of the target protein, involving large conformational changes that 'close' the CRL4-CRBN E3 ubiquitin ligase prior to recruitment of the neosubstrate. At Neomorph, we have established many glue systems outside of the canonical ‘closed’ cereblon / G-loop system. In this presentation, I will describe the process by which we have enabled multiple novel glue systems, including ‘open’ cereblon, and further unprecedented E3 ligase systems where we went from apo E3 ligase to functional glue.