ZZ151 is an effective and selective SOS1 PROTAC with in vivo anti-tumor efficacy against KRAS-mutant cancers. This compound induces rapid and specific degradation of SOS1 and exhibits strong anti-proliferative activity against a wide range of KRAS mutation-driven cancer cells. In murine xenograft models with KRASG12D and G12V mutations, ZZ151 demonstrates superior anticancer activity. It represents a promising lead compound for developing new chemotherapeutic agents targeting KRAS mutations.