A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRAS^G12C Inhibitor

AMG510, as the first approved inhibitor for KRAS^G12C mutation, has shown promising efficacy in nonsmall-cell lung cancer and colorectal cancer harboring KRAS^G12C mutation. However, the moderate response rate and the rapid emergence of acquired resistance limit the therapeutic potential of AMG510, highlighting the need for the development of combination strategies. Here, we observed the suppression of RAS-MAPK signaling induced by AMG510 was prolonged and enhanced by SOS1 knockdown. Thus, we design, synthesize, and characterize a potent and specific SOS1 degrader <b>23</b>. Compound <b>23</b> showed efficient SOS1 degradation in KRAS-driven cancer cells and achieved significant antiproliferative potency. Importantly, the combination of <b>23</b> with AMG510 suppressed RAS signaling feedback activation, showing synergistic effects against KRAS^G12C mutant cells <i>in vitro</i> and <i>in vivo</i>. Our findings demonstrated that KRAS^G12C inhibition plus SOS1 degradation as a potential therapeutic strategy to improve antitumor response and overcome acquired resistance to KRAS^G12C inhibitor.