A '2-in-1' PROTAC Folds the Cereblon Ligand into the HDAC8 Cap to Shrink the Degrader
- Instead of tethering two ligands, the cereblon-binding motif is built into the capping group of an HDAC8 inhibitor, so one structural element engages both proteins.
- Versus the group's first-generation degrader, the compact analogs are smaller, more selective and more drug-like.
- They degrade HDAC8 potently in vivo.
💡 Points
Most of us accept PROTAC bulk as a tax; fusing the E3 ligand into the warhead's cap group attacks that directly and is a transferable idea for other zinc-enzyme targets. The question I'd press is whether the shared motif compromises either binding event or cereblon neosubstrate selectivity. If in vivo degradation holds with better properties, the 'linkerless' direction deserves more attention.
A 2-in-1 Strategy for the Discovery of Compact HDAC8 Protac Degraders ↗