Systematic molecular glue drug discovery with a high-throughput effector protein remodeling platform

ABSTRACT Realising the promise of new medicines that operate through a targeted molecular glue-induced degradation mechanism requires systematic tools that can uncover the relevant principles of neomorphic protein-protein interactions. Whilst some monovalent glue degraders have been found through serendipity, the rules for small molecule attributes and the pairs or complexes of proteins that are amenable to drug-induced proximity control remain poorly articulated. Here we introduce a new approach to address this by using programmed libraries of intramolecularly edited proteins to expand protein surface landscapes and trigger new druggable interactions. We show that effector proteins, such as the E3 ligase Cereblon, can be engineered to provoke neomorphic activity by inducing the degradation of new client proteins and that these de novo interactions provide a blueprint from which new small molecule degraders can be built. As a demonstration of the approach, we use the platform to identify new non-IMiD molecular glue degraders of the oncology target GSPT1. SUMMARY Molecular glues are a highly important and promising new form of therapeutic agent, but rationalising their discovery has so far been impossible GlueSEEKER screening enables prospective monovalent drug discovery by using high-throughput deep mutational scanning to re-engineer the function of effector proteins like E3 ligases We used this approach to enable the computational discovery of small molecule glues which degrade the oncology target GSPT1 and show how the technology can be used across new targets