Linker design rules for EGFR ATP-allosteric bivalent inhibitors
- Studies ATP-site/allosteric bivalent EGFR inhibitors, where two ligands bound in neighbouring pockets are joined by a linker.
- A systematic SAR series shows that both linker length and attachment points can drive large potency improvements.
- Structural data and simulations point to maximal linker flexibility as the key design criterion, offering a framework that extends to fragment-based drug discovery.
💡 Points Based on the abstract
Linker flexibility winning out is the interesting part: for a bivalent ATP-site/allosteric binder, I'd expect a rigid, pre-organized linker to pay off, so this suggests the two pockets are only loosely coupled. Attachment-point sensitivity is what I'd mine first. I'd want selectivity over WT EGFR and the molecular weight/permeability cost before calling it tractable.