Design, synthesis and biological evaluation of KRASG12C-PROTACs

•The first KRASG12C-PROTACs based on the AMG-510 were reported as KRASG12C degraders.•A series of KRASG12C-PROTACs have degradation activity and potently inhibit downstream p-ERK with potency over AMG-510.•Active PROTACs have overall anti-proliferative activities against NCI-H358 (KRASG12C) and MIA PaCa-2 (KRASG12C).•SARs study showed that VHL may be more suitable as E3 ligase than CRBN and linkers have a great impact on PROTACs activity.•These results provide clues for structural optimization of KRASG12C-PROTACs.