Molecular glue CELMoD compounds are regulators of cereblon conformation

Abstract

Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN’s thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo–electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)–CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

“…Unlike most other DCAF proteins, DCAF16 does not contain a canonical WD40 propeller 34 , and instead is a relatively unstable protein predicted to be largely unstructured. It is noteworthy that our structural studies suggest a high degree of conformational flexibility, similar to findings from studies of CRBN [35][36][37] , and we speculate that such structural plasticity in a ligase can facilitate glue activity. A central challenge for the development of molecular glue degraders is the need for approaches for rational drug design and discovery 38 .…”

Advancing Strategies for Proteolysis-Targeting Chimera Design

“…The linker has a key impact on the molecular glue function. Recently, the structural mechanism for this function of IMiDs was elucidated . The authors studied three molecules with different activities for ubiquitinylation of the neosubstrate Ikaros: compounds 12 (moderate), 55 (CC-220, potent), and 56 (CC-92480, most potent).…”

“…Recently, the structural mechanism for this function of IMiDs was elucidated. 79 The authors studied three molecules with different activities for ubiquitinylation of the neosubstrate Ikaros: compounds 12 (moderate), 55 (CC-220, potent), and 56 (CC-92480, most potent). Their data showed that pomalidomide induced 20% of CRBN to be closed, and compound 55 induced 50% of CRBN to be closed.…”

Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence

“…Finally, MGDs may also function from an allosteric site . In this case, the small molecule does not participate directly in the interaction.…”

“…259 Finally, MGDs may also function from an allosteric site. 260 In this case, the small molecule does not participate directly in the interaction. Rather, it exposes or modifies a PPI interface by binding to a distant pocket that stabilizes a (non-native) conformation of the protein.…”