Discovery of a Potent and Selective KRAS G12D Degrader based on PROTAC Degradation.

KRAS-G12D has long been regarded as an intractable therapeutic target due to the flat binding pocket and its strong affinity for GTP/GDP. Proteolysis-targeting chimera (PROTAC) is a revolutionary drug discovery strategy that, by virtue of its unique pharmacological mode of action, provides more options for targeting undruggable targets. In this study, we designed and synthesized 20 novel KRAS G12D PROTACs based on the MRTX1133 derivative. Through systematic exploration of linker structure-activity relationship and multi-cell line screening, compound VI-1 exhibited significant KRAS G12D degradation activity in PANC-0203 cells, achieving 69% effective degradation at 10 μM. Notably, the preferred compounds exhibited significant selectivity for other KRAS mutations and normal cells. This work provides an important lead compound for developing highly selective KRAS G12D PROTACs and warrants further exploration in the context of drug-likeness optimization.