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

Abstract Pancreatic cancer driven by the KRASG12D 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 KRASG12D inhibitor to a CRBN ligand. It selectively degrades KRASG12D (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 KRASG12D 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 KRASG12D mutants, establishing a groundbreaking approach for KRAS-driven malignancies.