Discovery and Optimization of Isoform Selective ULK1 Degraders to Enhance Antitumor Activity in KRAS-Mutant Cancer

Abstract Selective targeting of ULK1 represents a promising approach to overcome autophagy-mediated resistance in KRAS-driven cancers. However, achieving selectivity over the closely related ULK2 isoform with ATP-competitive inhibitors remains challenging due to the high sequence homology within their kinase domains. Here, we describe the design, synthesis, and structure−degradation relationship studies of two cereblon-recruiting ULK1 degraders, MR-9034 and MR-9036. Structure-guided optimization led to the discovery of MR-9036 as a potent and selective ULK1 PROTAC that degrades ULK1 without affecting ULK2 or IMiD neo-substrates. Cellular and biophysical studies confirm ternary complex formation and proteasome-dependent degradation. Compared with the clinical ULK1/2 inhibitor DCC-3116, MR-9036 produces sustained autophagy suppression following compound washout. In KRASG12C-mutant NSCLC models, ULK1 degradation enhances the antiproliferative activity of sotorasib. Pharmacokinetic/pharmacodynamic (PK/PD) studies in mice support in vivo feasibility. These findings establish selective ULK1 degradation as a chemical strategy to interrogate ULK1 biology and enhance therapeutic response in KRAS-driven cancers.