An allosteric site on the E3 ligase adapter cereblon can be targeted to modulate the efficacy of cereblon in targeted protein degradation applications.

An allosteric site on the E3 ligase adapter cereblon can be targeted to modulate the efficacy of cereblon in targeted protein degradation applications.

Stabilization of cereblon (CRBN)/neosubstrate complexes with molecular glues followed by degradation of those neosubstrates is an emerging strategy in drug discovery with compelling potential to targe...

The majority of clinical degraders utilize an immunomodulatory imide drug (IMiD)-based derivative that directs their target to the E3 ligase receptor …

An allosteric site on the E3 ligase adapter cereblon can be targeted to modulate the efficacy of cereblon in targeted protein degradation applications.

Cereblon (CRBN) is one of the most widely co-opted E3 ligase substrate receptor proteins in targeted protein degradation (TPD), and several CRBN-recruiting degraders are currently in late-stage preclinical evaluation. While the diversity of CRBN-recruiting moieties has rapidly expanded, the glutarimide ring has remained largely conserved in these ligands. Glutarimides can form during protein cleavage events via the intramolecular cyclization of glutamine within the protein backbone. Inspired by this biological mechanism, we developed CRBN-recruiting prodegraders by replacing the glutarimide in parent degraders with uncyclized glutamine analogs. Prodegraders derived from a potent, cytotoxic GSPT1 degrader exhibited in cellulo cyclization, resulting in GSPT1 degradation. Optimization of the prodegrader scaffold revealed that glutarimide cyclization rates─and consequently, degradation kinetics─were tunable, with the most optimized prodegrader displaying degradation efficacy and cytotoxicity comparable to the parent, glutarimide-containing GSPT1 degrader. Furthermore, this prodegrader strategy can be readily applied to other known CRBN-based molecular glues and PROTACs. In contrast to conventional glutarimide-containing degraders, the amide of the prodegrader scaffold provides an accessible conjugation handle for stimulus-sensitive groups. We show that prodegraders can be conjugated to and released in vitro from a photolabile protecting group and a commonly used cathepsin-cleavable degrader–antibody conjugate (DAC) linker. Therefore, these prodegrader scaffolds introduce a generalizable conjugation strategy for CRBN-recruiting degraders to DAC linkers, eliminating the need for extensive degrader modifications to incorporate a conjugation handle. Overall, these findings establish the feasibility of utilizing glutamine analogs as a CRBN-recruiting prodegrader strategy and highlight their potential application in targeted drug delivery systems.

Due to challenges in studying molecular interactions of CRBN, identification of CRBN based molecular glues has remained underexplored. Here, Bailey et al designed an easy-to-handle CRBN construct and ...

ConspectusThe E3 ligase substrate adapter cereblon (CRBN) has garnered widespread interest from the research laboratory to the clinic. CRBN was first discovered for its association with neurological d...

C-Terminal cyclic imides are posttranslational modifications on proteins that are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN). Despite the observation of these modificati...

Molecular glue degraders that bind the E3 ligase adaptor cereblon are clinically precedented drugs used to treat cancer. Highly potent next-generation degraders are in development that target difficul...

Cereblon (CRBN) is the target of thalidomide derivatives1 that achieve therapeutic efficacy against some haematologic neoplasias2–4 by recruiting neosubstrates for degradation5–7. Despite the intense investigation of orthosteric thalidomide derivatives, little is known about alternate binding sites on CRBN. Here we report an evolutionarily conserved cryptic allosteric binding site on CRBN. Small-molecule SB-405483 binds the allosteric site to cooperatively enhance the binding of orthosteric ligands and alter their neosubstrate degradation profiles. A survey of over 100 orthosteric ligands and their degradation targets reveals trends in the classes of compounds and neosubstrates in which degradation outcomes are enhanced or inhibited by SB-405483. Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBNopen to a novel CRBNint and increasing the CRBNclosed state. The discovery of a cryptic allosteri

Nature Structural & Molecular Biology, Published online: 20 January 2026; doi:10.1038/s41594-025-01738-8Annunziato, Quan and Donckele et al. identify G3BP2 (Ras–GAP SH3 domain-binding protein 2) as a molecular glue-induced neosubstrate of the CRL4CRBN E3 ubiquitin ligase. The CRBN–glue neosurface uses a molecular surface mimicry mechanism to recruit and degrade G3BP2 in a compound-dependent manner.

Efficiency metrics are useful in medicinal chemistry to track small molecule progress in lead optimization (LO). Molecular glue degraders are small molecules that mediate targeted protein degradation ...