We noted here that the disclosed water replacing compounds are somewhat suboptimal, as they introduce a repulsion with the native conformation of Thr58 (manifested with the Thr58 side chain conformation change). To date, most of the reported SII-P binders are covalent inhibitors targeting KRAS(G12C) (and more recently G12S and G12R). Therefore, it may be that while maintaining the inhibitor reactivity to the covalent linkage to the position 12, located near to this conserved water region, has hindered the water-targeting among these compounds. Obviously, after the covalent reaction has taken place, the consideration of the initial negative water impact on compound efficacy is less profound.