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Updated: May 6, 2026

Resin-Assisted Capture Coupled with Isobaric Tandem Mass Tag Labeling for Multiplexed Quantification of Protein Thiol Oxidation
Published on: June 21, 2021
Enabling Access to sp3-Enriched Targeted Protein Degraders via Redox-Neutral Radical Cross-Coupling
Philipp Neigenfind1, Clara Gathmann1, Emily C Cherney2
1Department of Chemistry, Scripps Research, San Diego, California, USA.
Abstract:
Cullin-RING Ligase 4 Cereblon (CRL4CRBN)-mediated targeted protein degradation (TPD) via cereblon (CRBN) E3 ligase modulatory drugs (CELMoDs) or ligand-directed degraders (LDDs) represents a new modality in modern drug discovery. However, the CRBN-binding portion of these degraders has been limited to flat, rigid architectures of conventional glutarimide scaffolds. This study presents a modular route to C3(sp3)-C(sp3) linked glutarimides via a redox-neutral cross-coupling/palladium-catalyzed hydrogenation sequence. This two-step protocol is operationally simple, chemoselective, and broadly tolerant of diverse functional groups. It delivers sp3-rich, three-dimensional scaffolds that access previously untapped chemical space. The resulting building blocks are ready for immediate use in the CELMoD and LDD arena and provide a versatile platform for next-generation TPD design. Preliminary studies of BRD4-targeting LDDs derived from C3(sp3)-C(sp3) linked glutarimides demonstrate CRBN-dependent degradation of BRD4, underscoring their translational potential.
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