Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing a privileged rewiring of cellular biochemistry. We hypothesized that high-throughput chemical synthesis could be used to alter the composite surface topology of a protein-ligand complex at scale, allowing for the prospective discovery of structural modifications that transform a ligand into a CIP. Selecting a ligand for the transcriptional co-activator, ENL, as proof of concept, we synthesized 3,163 analogs in parallel and then screened each for the acquired ability to induce ENL degradation. This effort revealed a pyrrolidine spirosuccinimide-bearing analog, dHTC1, that elicits potent, selective, and stereochemistry-dependent degradation of ENL in vitro and in vivo. Further study revealed that dHTC1 functions through CRL4CRBN, the ubiquitin ligase complex responsible for the therapeutic effects of thalidomide analogs, despite possessing minimal intrinsic affinity for the ligase. Instead, binding to ENL templates a projection of its spirosuccinimide group that allows the ENL:dHTC1 complex to bind CRL4CRBN with high affinity and cooperativity, leveraging a distributed interface of ENL-CRBN interactions. Extending this chemistry to identify BRD4 degraders, we altogether present a facile method to prospectively transform ligands into chemical inducers of proximity and, by revealing a new mechanism to elicit CRL4CRBN-dependent degradation, point toward an expanded chemical space to coopt this therapeutically important ubiquitin ligase complex.