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

Thalidomide, initially marketed as a sedative and anti-emetic, was withdrawn in the 1960s due to catastrophic teratogenic effects. Decades later, thalidomide was reconsidered as an anticancer agent, resulting in FDA approval against multiple myeloma. This success spurred the development of structural analogs lenalidomide and then pomalidomide as cancer therapies (immunomodulatory imide drugs, IMiDs). Subsequent landmark studies have revealed that IMiDs act as molecular glue degraders, co-opting the E3 ubiquitin ligase cereblon (CRBN) to induce the polyubiquitination and proteasomal degradation of several proteins (e.g., 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.