Assessing and categorizing health-related quality of life outcomes in children and youth with acquired brain injury in outpatient rehabilitation.

The clinical success of drugs such as thalidomide, lenalidomide, and pomalidomide has invigorated efforts to design next-generation protein degraders using the underlying mechanism of Cereblon E3-ligase (CRBN) recruitment. These small molecules act as either molecular glues, inducing or stabilising interactions between CRBN and substrate proteins, or as key ligands within bifunctional architectures known as PROTACs (Proteolysis Targeting Chimeras). PROTACs that utilise CRBN chemically tether an E3-ligase-binding fragment to a ligand for a target protein, forming a degrader that directs disease-relevant proteins to CRBN for ubiquitination and subsequent proteolysis. The success of Cereblon E3 Ligase Modulatory Drugs (CELMoDs) in oncology and immunology underscores the need for versatile platforms to access structurally diverse and potent CRBN binders. At the heart of most CRBN-targeting molecules lies a glutarimide scaffold, a six-membered cyclic imide that binds to a small hydrophobic pocket (tri-Trp pocket) in the thalidomide-binding domain (TBD) of CRBN. The amine nitrogen of the glutarimide is bound to the rest of the degrader structure via a ‘connecting group’ (Fig. ). Commonly employed connecting groups include isoindolinone (utilised in lenalidomide, the PROTAC vepdegestrant and the molecular glue degrader mezigdomide), phthalimides (used in thalidomide and pomalidomide) and anilines (such as in gridegalutamide) (Fig. ). In the pursuit of improved properties, designers have looked to a wide variety of architectures to constitute this connecting group, with structures like benzindolone, benzimidazolone and phthalazone featuring in a number of degrader scaffolds, as well as pyridyl amides and poly-substituted isoindolinones. DEG-35 as an example of a typical glutarimide-containing CELMoD or CRBN-dependent molecular glue degrader. Typical connecting groups in molecular glue degraders/CELMoDs and PROTACs. Previously explored approaches to incorporate the connecting heterocycle to the glutarimide scaffold. Our late-stage organocatalytic ‘glutarimidation’ cascade with applications to CRBN binder synthesis.