Cereblon Allosteric Inhibition: VVD-105917 and Cys287 Targeting

bioRxiv USA

Overview

Researchers have identified a cryptic allosteric pocket at Cys287 of cereblon (CRBN) that can be targeted by covalent ligands to inhibit protein degradation. The lead compound, VVD-105917, traps CRBN in an inactive open conformation, providing a mechanism to override IMiD/CELMoD-driven neosubstrate degradation.

In Depth

Key Findings

The study identifies a cryptic allosteric pocket distal to the orthosteric site of cereblon (CRBN) that can be engaged via covalent ligands. The lead compound, VVD-105917, acts as a pan-inhibitor of neosubstrate degradation driven by IMiDs and CELMoDs. This discovery demonstrates that the Cys287 site is mechanistically sign-switchable, as a different recently reported ligand at the same pocket promotes rather than blocks the closure of the protein.

Technical Details

Using cysteine-directed chemoproteomic screening, the researchers identified ligands that engage Cys287. Cryo-EM structures reveal that covalent engagement of Cys287 traps CRBN in an open, inactive conformation. This process resolves a sensor loop and N-terminal segment that were previously unobserved. Sequential incubation experiments indicate that the conformational outcome depends on the order in which ligands are added, proving that allosteric engagement can override the closure induced by potent CELMoDs.

Background & Context

Thalidomide-derived CRBN modulators are clinically impactful targeted protein degradation therapeutics. These agents redirect the CRL4-CRBN E3 ubiquitin ligase to degrade disease-driving neosubstrates. However, all current IMiDs and CELMoDs target a single orthosteric pocket, leaving the broader conformational landscape of CRBN largely unexplored for pharmacological use.

Significance & Outlook

These findings establish that covalent chemoproteomics is a viable strategy for discovering and controlling conformational switches in E3 ligases. By targeting the allosteric Cys287 pocket, it is possible to modulate the activity of CRBN independently of the orthosteric site, offering a new method for controlling the degradation of neosubstrates.

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