Modulating protein homeostasis using small-molecules is an exciting new area for therapeutics discovery. Inducing target degradation using bifunctional molecules has been the predominant approach to this field. We will describe a set of new tools that allows us to probe E3 ligase interactions without requiring ligands to targets apriori. Phenotypic assays that use DNA-encoded libraries (DELPhe) can scan chemical space for compounds that modulate E3 ligases in specific and interesting ways. Examples of both single-target and multiple-target perturbations identified on DELPhe will be presented, including a machine learning formalism to evolve pleiotropic perturbations towards desirable goals.