The design and synthesis of selective and potent selenium-containing KRAS^G12D inhibitors

KRAS^G12D is the most common KRAS mutation and a promising therapeutic target for various type cancers, particularly pancreatic cancer. In this study, we employed a structure-based drug design approach to develop a series of 2-aminobenzo[b]selenophene-3-carbonitrile derivatives as potent and selective KRAS^G12D inhibitors. The representative compound (R)-5a effectively and selectively inhibited the proliferation of KRAS^G12D harboring AsPC-1 cells, with an IC₅₀ value of 10 nM, while sparing other KRAS^mut and KRAS^WT cell lines. Furthermore, compound (R)-5a suppressed KRAS downstream signaling, including ERK/MAPK pathway and induced apoptosis and G0/G1 phase arrest in a dose-dependent manner. In addition, compound (R)-5a has good pharmacokinetic properties compared to MRTX1133. These findings demonstrate (R)-5a as a promising lead compound for the development of KRAS^G12D selective inhibitor.