Conversely with the G12C targeting compounds, the reported potent G12D binders are lacking the conserved water displacing cyanomethyl-group, which was observed not to be beneficial for these non-covalent binders. Initially Wang et al. published six structures (PDB IDs: 7RPZ; 7RT1; 7RT2; 7RT3; 7RT4; 7RT5) , which all display the Thr58 associated conserved water (Table ; Figure ; Figure ). Moreover, Wang et al. reported that the 8-ethynyl of the MRTX1133 is actively participating to the conserved water interaction network (Figure ).