Bicyclobutane warheads deliver the first covalent PARG inhibitors
- Starting from reversible quinazolinedione PARG inhibitors, the team added electrophiles to reach Cys872 inside the catalytic pocket.
- Enone and hydrazide warheads worked, but a bicyclo[1.1.0]butane hydrazide gave a compound with potent activity, milder reactivity and cleaner covalent labeling.
- A hybrid with a reversible quinoline series produced a covalent BCB-carboxamide inhibitor with nanomolar activity in PARG-sensitive cancer cells.
💡 Points Based on the abstract
BCB warheads are attractive because strain-release reactivity is tunable and less promiscuous than acrylamides. What the preprint needs is proteome-wide selectivity (chemoproteomics) and a jump in residence time over the reversible clinical-stage PARG series. Without that, I can't say covalency buys more than a longer-lived reversible binder would.
📄 Paper · chemRxiv ↗ Expanding the Covalent Warhead Toolbox: Discovery of the First Covalent PARG Inhibitors Using Bicyclo[1.1.0]butane-Based Warheads