BI-2852

BI-2852 is a potent, small molecule KRAS inhibitor developed by Boehringer Ingelheim that targets the switch I/II pocket (SI/II-pocket) on KRAS with nanomolar affinity. Unlike covalent KRAS G12C inhibitors that bind to the inactive state of the protein, BI-2852 binds to a pocket present in both the active (GTP-bound) and inactive (GDP-bound) forms of KRAS. The compound demonstrates a ten-fold higher affinity for the KRAS G12D mutant compared to wild-type KRAS. Mechanistically, BI-2852 sterically blocks the interaction of KRAS with guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and downstream effectors such as RAF. This comprehensive blockade leads to the inhibition of downstream signaling pathways and exerts antiproliferative effects in KRAS-mutant cancer cells. BI-2852 is currently in preclinical development for the treatment of neoplasms driven by KRAS mutations, particularly those harboring the G12D mutation.