Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations

Abstract

Regulating SOS1 functions may result in targeted pan-KRAS therapies. Small-molecule SOS1 inhibitors showed promising anticancer potential, and the most advanced inhibitor BI 1701963 is currently under phase I clinical studies. SOS1 agonists provide new opportunities to treat cancer; however, the underlying mechanisms still warrant investigation. We here report the discovery of the first SOS1 PROTACs designed uniquely by connecting a VHL ligand to the reported SOS1 agonist, ensuring that the observed inhibitory activity results from degraders. The best compound <b>9d</b> induced SOS1 degradation in various KRAS-driven cancer cells and displayed superior antiproliferation activity compared to the agonist itself. Tumor xenograft study clearly showed the promising antitumor potency of <b>9d</b> against human lung cancer. This study provides good evidence of using agonists to design SOS1 PROTACs and demonstrates that targeted SOS1 degradation represents an effective therapeutic strategy for overcoming KRAS-driven cancers.