ZJK-807: A Selective PROTAC Degrader of KRASG12D Overcoming Resistance in Pancreatic Cancer

Pancreatic cancer driven by the KRAS^G12D mutation faces therapeutic challenges from KRAS undruggability and acquired resistance to inhibitors like MRTX1133 via secondary mutations (e.g., Q95/Y96). Here, we report ZJK-807, a novel cereblon (CRBN)-based proteolysis-targeting chimera (PROTAC), conjugating a KRAS^G12D inhibitor to a CRBN ligand. It selectively degrades KRAS^G12D (DC₅₀ = 79.5 ± 5.4 nM in AsPC-1 cells) with minimal impact on wild-type KRAS or other mutants (G12C/S/V, G13D), inducing mutant-specific cytotoxicity. Critically, ZJK-807 overcomes secondary mutation resistance by degrading mutant KRAS^G12D and suppressing resistant cell growth where MRTX1133 fails. Transcriptomic analysis revealed that ZJK-807 suppresses RAS/MAPK signaling and uniquely modulates TNF signaling and eukaryotic ribosome biogenesis, suggesting distinct mechanistic advantages. In vivo, ZJK-807 (30 mg/kg, subcutaneous) achieved 47% tumor growth inhibition in AsPC-1 xenografts with favorable pharmacokinetics. This study presents a CRBN-based PROTAC to selectively target and degrade resistant KRAS^G12D mutants, establishing a groundbreaking approach for KRAS-driven malignancies.