Development of SOS1 Inhibitor-Based Degraders to Target <i>KRAS</i>-Mutant Colorectal Cancer
Yujia Bian, Diego Alem, Francisca Beato, Tara L. Hogenson, Xinrui Yang, Kun Jiang, Jianfeng Cai, Wen Wee, Martín E. Fernández-Zapico, Aik Choon Tan, Nicholas J. Lawrence, Jason B. Fleming, Yu Yuan, Hao Xie
Abstract
Direct blockade of KRAS driver mutations in colorectal cancer (CRC) has been challenging. Targeting SOS1, a guanine nucleotide exchange factor, has arisen as an attractive approach for KRAS-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 IC50 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 KRAS-mutant CRC.