Molecular glue degraders versus PROTACs: a novel paradigm in targeted protein degradation.

Many proteins that cause cancer are still out of reach for regular drugs because they do not have the right structure for small molecules to bind to. Targeted protein degradation (TPD) is a new way to do things. Instead of blocking these proteins, it takes over the cell's own disposal system, the ubiquitin-proteasome system, to get rid of them completely. Two main strategies have emerged: molecular glue degraders, which are small compounds that help an E3 ligase find and tag a target protein, and PROteolysis TArgeting Chimeras (PROTACs), which are engineered bifunctional molecules that physically connect a target to a degradation pathway. Both have shown real promise in early clinical work. PROTACs that target Bruton's tyrosine kinase have shown great response rates in B-cell cancers, and molecular glues that target Ikaros family proteins (IKZF1/3) are still helping people with blood cancers. But there are still problems. PROTACs have trouble dissolving and getting into the body through the mouth. The "hook effect" can make them less effective at higher doses, and both strategies rely heavily on a small number of E3 ligases. To make progress, we need to add more enzymes to our toolkit, design molecules better, and get better data from clinical trials. With cooperation from academia, industry, and regulators, TPD could significantly expand the druggable proteome and transform cancer treatment.