Discovery of ZJK-366 as a potent and selective PROTAC degrader of KRAS^G12D protein for the treatment of cancer

Abstract

The KRAS^G12D mutation, which occurs in nearly half of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) cases, has demonstrated considerable promise as a target for cancer therapy. In this study, we report a series of VHL-recruiting proteolysis targeting chimeras (PROTACs) targeting KRAS^G12D based on the analogues of MRTX1133. Through extensive structure–degradation relationship (SDR) studies involving the optimization of linker parameters, E3-binding ligand, and KRAS^G12D warhead, ZJK-366 is obtained as a representative compound that can selectively, effectively, and sustainably degrade KRAS^G12D in a dose-, time- and ubiquitin–proteasome system-dependent manner. ZJK-366 also inhibits the growth of KRAS^G12D mutant cell lines. Moreover, ZJK-366 is capable of overcoming resistance induced by secondary mutations. ZJK-366 shows attractive pharmacokinetic properties and effectively and safely inhibits tumor growth in the cell line-derived xenograft model in a dose-dependent manner. These results underscore the potential of PROTAC-mediated KRAS^G12D degradation as a strategy for treating KRAS mutation-driven cancers.

Keywords

Proteolysis targeting chimera (PROTAC) / KRAS^G12D / KRAS-driven cancers / Colorectal cancers (CRC)

References

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