Longer semi-rigid linkers drive VHL-based HDAC6 degraders with antileukemic activity
- A solid-phase route enabled systematic variation of VHL ligand, exit vector and linker in vorinostat-derived HDAC6 PROTACs.
- Longer, semi-rigid linkers gave the best degradation; the lead compounds degraded HDAC6 preferentially in MM.1S and MV4-11 cells.
- A matched non-degrading control with similar HDAC inhibition was clearly less antiproliferative, pointing to degradation itself as the driver.
💡 Points
The non-degrading control with matched enzyme inhibition is the kind of experiment that separates degradation from plain inhibition, and it favors the PROTAC. Preferential, not exclusive, HDAC6 selectivity from a vorinostat-like warhead is the weak point; a more isoform-selective ligand might sharpen it.