As the effect of sotorasib on the wild-type RAS isoforms was much weaker than that for adagrasib, we next tested if KRAS mutations in positions G12, G13, and Q61 would alter the accessibility of the SII-pocket for both inhibitors (Figure ). In the QRET nucleotide exchange assay, KRAS mutations G13D and Q61L had no significant effect on adagrasib inhibitory activity over KRAS(WT), while G12D and G12V mutations increased the IC50 value approximately 10-fold in comparison to KRAS(WT) (Table ). This was confirmed by the TSA, in which adagrasib stabilization was more pronounced with KRAS(G13D) and KRAS(Q61L), compared to KRAS(G12V) (Figure ). The weak effect of sotorasib on nucleotide exchange observed for KRAS(WT) was similar with all four tested KRAS mutants, indicating low affinity against all non-G12C KRAS proteins (Figure , Table ). However, at a high sotorasib concentration (100 µM) a clear stabilization for KRAS(G12V), KRAS(Q61L), and KRAS(G13D) was monitored (Figure ).