The synthetic landscape of cereblon (CRBN) binders: from thalidomide to emerging chemotypes

, the transcription factors IKZF1/3). From 2015 onwards, IMiDs have also been widely incorporated into the design of PROteolysis-TArgeting Chimeras (PROTACs) to recruit additional target proteins to CRBN and trigger target depletion. IMiDs have proven particularly suited for PROTAC development due to their efficient co-opting of CRBN and structural simplicity. Intense medicinal chemistry and chemical biology efforts have expanded CRBN-binding chemotypes far beyond classical thalidomide analogues, yielding a diverse array of molecular glues and PROTAC handles with tailored neosubstrate profiles and properties. In this review, we systematically organize the synthetic landscape of CRBN binders from a chemotype-centric perspective. After providing a historical overview of thalidomide, we classify CRBN binders into four major families: phthalimido glutarimides (thalidomide derivatives), isoindolinone-2-yl glutarimides (lenalidomide-type scaffolds), glutarimides linked to alternative heterocyclic or aromatic motifs, and emerging glutarimide-free CRBN modulators. For each class, representative examples are discussed alongside modular routes and recurrent derivatization vectors that have enabled both clinically used IMiDs and next-generation molecular glue degraders and PROTACs. By integrating structural insights with synthetic strategies, we provide a structure-guided roadmap for chemists and chemical biologists seeking to navigate, rationally expand, and functionally tailor the growing chemical space of small-molecule CRBN binders.