Molecular Glue Discovery: Current and Future Approaches

The intracellular interactions ofbiomolecules can bemaneuveredto redirect signaling, reprogram the cell cycle, or decrease infectivityusing only a few dozen atoms. Such "molecular glues,"which can drive both novel and known interactions between proteinpartners, represent an enticing therapeutic strategy. Here, we reviewthe methods and approaches that have led to the identification ofsmall-molecule molecular glues. We first classify current FDA-approvedmolecular glues to facilitate the selection of discovery methods.We then survey two broad discovery method strategies, where we highlightthe importance of factors such as experimental conditions, softwarepackages, and genetic tools for success. We hope that this curationof methodologies for directed discovery will inspire diverse researchefforts targeting a multitude of human diseases.