A covalent ligand at cereblon's cryptic Cys287 locks the E3 ligase open and blocks IMiD-driven degradation
- Cysteine-directed chemoproteomic screening found covalent ligands for Cys287, an allosteric pocket far from the thalidomide-binding site.
- Lead VVD-105917 broadly blocks degradation of neosubstrates driven by IMiDs and CELMoDs.
- Cryo-EM shows it traps cereblon in its open, inactive state, and ligand order matters. A previously reported ligand at the same site promotes closure instead, so the pocket is 'sign-switchable'.
💡 Points
Every CRBN drug so far sits in one orthosteric pocket, so a covalent handle that controls the open/closed switch is a genuinely new knob. A pan-inhibitor is an excellent tool to dissect degrader mechanisms and rescue off-target degradation. A site that can push either way also means a degrader-enhancing ligand might be hiding in the same pocket. This is a preprint, so wait for review.
Allosteric covalent inhibition of cereblon through cryptic cysteine targeting ↗