A trimethyl lock successfully stabilizes a nascent Michael acceptor for prodrug applications.

5-Hydroxy-γ-pyrone-based Michael acceptors have repeatedly registered as hits in screens for inhibiting key therapeutic targets, but their aqueous instability has prevented further development. Here, we report a method to stabilize such an inhibitor of STAT3 with a trimethyl lock until reduction by hNQO1, an enzyme typically overexpressed in hypoxic tumors.