Protein–protein interactions (PPIs) govern all biological processes. Some small molecules modulate PPIs through induced protein proximity. In particular, molecular glue degraders are monovalent compounds that orchestrate interactions between a target protein and an E3 ubiquitin ligase, prompting the proteasomal degradation of the former. This and other pharmacological strategies of targeted protein degradation (e.g. proteolysis-targeting chimeras – PROTACs) overcome some limitations of traditional occupancy-based therapeutics. Here, we provide an overview of the “molecular glue” concept, with a special focus on natural and synthetic inducers of proximity to E3s. We then briefly highlight the serendipitous discoveries of some clinical and preclinical molecular glue degraders, and discuss the first examples of intentional discoveries. Specifically, we outline the different screening strategies reported in this rapidly evolving arena and our thoughts on future perspectives. By mastering the ability to influence PPIs, molecular glue degraders can induce the degradation of unligandable proteins, thus providing an exciting path forward to broaden the targetable proteome.

Significance: Haploidy is a critical advantage for studies on gene function, because only one allele needs to be mutated to yield a phenotype. That is why yeast has led genetic screenings in recent decades. All mammalian cells except germ cells contain two or more sets of chromosomes. Recently, several mammalian haploid cell lines have been obtained; however, the haploid state is unstable, and cultures become progressively enriched in diploid cells. Here we reveal that chromosome segregation takes longer in mammalian haploid cells than in their diploid counterparts, and is followed by an increase in spontaneous cell death. By deleting p53, we can rescue the viability of haploid cells and thereby stabilize the haploid state in mammalian somatic cells.