GTP-Competitive Inhibitors of RAS Family Members

Early efforts to therapeutically target RAS focused away from the GTP-binding site because it was assumed that small molecule inhibitors could never compete with the picomolar binding affinity and micromolar cellular concentrations of GTP and achieve specificity for the RAS family members. Medicinal chemistry has evolved, providing new options for designing covalent compounds. Here, we review the theoretical basis for attempting to target the GTP-binding site of RAS using covalent chemistry and discuss proof-of-concept experiments.