BI-2852 (BI2852) is a novel and potent KRAS inhibitor that binds with nanomolar affinity to the SI/II pocket of KRAS, which is mechanistically distinct from covalent KRASG12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, BI-2852 blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS.

References: Proc Natl Acad Sci U S A. 2019 Aug 6;116(32):15823-15829.