Isoform-selective ULK1 PROTAC gives longer autophagy suppression than an inhibitor
- ATP-competitive inhibitors struggle to separate ULK1 from the near-identical ULK2, so the authors built cereblon-recruiting degraders instead.
- Structure-guided optimization gave MR-9036, which degrades ULK1 without touching ULK2 or IMiD neo-substrates, with ternary complex formation and proteasome dependence confirmed.
- After compound washout it kept autophagy suppressed longer than the clinical ULK1/2 inhibitor DCC-3116, with antitumor activity in KRAS G12C NSCLC models.
💡 Points
Selectivity between paralogs is where degraders can beat occupancy-driven drugs, and this is a clean example. What I'd check next is whether ULK2 compensation shows up in vivo, and whether washout durability holds in a model with realistic drug exposure rather than a pulse.