A macrocyclic BI-4020-based PROTAC degrades C797S-resistant EGFR
- HQY1480 is a PROTAC built on the macrocyclic fourth-generation EGFR inhibitor BI-4020, with the linker and E3 ligand optimized systematically.
- It degraded several clinically relevant EGFR mutants at low nanomolar concentrations, and proteomics showed no detectable off-target degradation.
- It outperformed BI-4020 in xenografts, including osimertinib-resistant models, and degraded EGFR in patient-derived xenografts.
💡 Points
Starting from a macrocycle rather than a classical TKI is the smart move: it sidesteps the poor PK and selectivity that EGFR PROTACs usually inherit from their warheads. I'd want to see how the degrader holds up against compound-specific resistance mutations, and whether the favorable PK survives scale-up beyond mouse.