Direct blockade of driver mutations in colorectal cancer (CRC) has been challenging. Targeting SOS1, a guanine nucleotide exchange factor, has arisen as an attractive approach for -mutant CRC. Here, we describe the development of novel SOS1 degraders and their activity in patient-derived CRC organoids (PDO). The design of these degraders as proteolysis-targeting chimera was based on the crystal structures of cereblon and SOS1. The synthesis used the 6- and 7-OH groups of a quinazoline core as anchor points to connect lenalidomide. Fifteen compounds were screened for SOS1 degradation. P7 was found to have up to 92% SOS1 degradation in both CRC cell lines and PDOs with excellent specificity. SOS1 degrader P7 demonstrated superior activity in inhibiting CRC PDO growth with an IC 5 times lower than that of SOS1 inhibitor BI3406. In summary, we developed new SOS1 degraders and demonstrated SOS1 degradation as a feasible therapeutic strategy for -mutant CRC.