Design, synthesis, and structural optimization of novel pan-KRAS degrader for the treatment of KRAS-mutant pancreatic cancer.

KRAS, a frequently mutated oncogene, has been demonstrated to harbor multiple mutant variants. Although KRAS G12C inhibitors have been successfully approved for clinical use, their efficacy remains limited by acquired resistance and narrow patient eligibility. Here, we leveraged the proteolysis-targeting chimera (PROTAC) strategy, utilizing a Cereblon (CRBN) ligand, to design a series of degrader molecules aimed at developing a pan-KRAS degrader. Systematic structural optimization identified a lead candidate, T3-10, which exhibited broad degradation across 12 common KRAS mutant subtypes, with particularly potent activity against G12A, G12R, G13D, and Q61H variants. As anticipated, in cellular proliferation inhibition assays, the optimized molecule significantly outperformed the previously reported compound ACBI-3. Mechanistically, T3-10 induced CRBN-mediated degradation of KRAS mutants while effectively suppressing ERK phosphorylation downstream of KRAS, thereby disrupting the MAPK signaling pathway. Critically, T3-10 demonstrated potential efficacy in overcoming acquired resistance. Furthermore, in vivo studies confirmed that T3-10 potently inhibited tumor growth in MIA PaCa-2 xenograft models, achieving a tumor growth inhibition rate of 60.86%. Our work presents a promising pan-KRAS PROTAC degrader and provides a strategic blueprint for developing diversified therapeutic approaches targeting KRAS mutations.