The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins 
which belong to the protein family of small GTPases that function as binary 
molecular switches involved in cell signaling. Activating mutations in RAS are 
among the most common oncogenic drivers in human cancers, with KRAS being the 
most frequently mutated oncogene. Although KRAS is an excellent drug discovery 
target for many cancers, and despite decades of research, no therapeutic agent 
directly targeting RAS has been clinically approved. Using structure-based drug 
design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with 
nanomolar affinity to a pocket, thus far perceived to be "undruggable," between 
switch I and II on RAS; 1 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, it 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.