Development of a Buchwald–Hartwig Amination\nfor an Accelerated Library Synthesis of Cereblon Binders

In\nrecent years, targeted protein degradation (TPD) has emerged\nas a powerful therapeutic modality utilizing both heterobifunctional\nligand-directed degraders (LDDs) and molecular glues (e.g., CELMoDs)\nto recruit E3 ligases for inducing polyubiquitination and subsequent\nproteasomal degradation of target proteins. The immunomodulatory drugs\nlenalidomide and pomalidomide bind to cereblon (CRBN), a substrate\nreceptor of the CRL4A E3 ligase complex, to initiate degradation of\nneosubstrates critical for cell survival. Recently, nonlenalidomide\nor pomalidomide CRBN binders, known as alternate glutarimides, have\ngained popularity, offering potential degraders with varying physicochemical\nproperties. Specifically, 3-substituted indazole derivatives have\nemerged as potent CRBN binders. We developed conditions for the direct\ncross-coupling of unprotected glutarimides with amines, streamlining\nthe synthesis of alternative CRBN binders. This manuscript describes\nthe rapid synthesis of 30 CRBN binders, their characterization as\npotential degraders and a cryo-EM structure of the CRBN/DDB1 with\na representative compound (<b>6</b>).