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 9d 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 9d 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.
The linker moiety of a proteolysis-targeting chimera (PROTAC) molecule plays a critical role in modulating the degradation activity, target selectivity, and physico-chemical properties. However, the basics and underlying mechanisms of chemical modifications of the linker structure causing dramatic changes in the PROTAC degradation activity warrant further investigation. Herein, we report the design and characterization of a highly potent and selective SOS1 PROTAC ZZ151. After systematically modifying the linker length and composition, we observed that subtle modification of just one atom of the linker moiety of ZZ151 resulted in remarkable changes in the formation of the ternary complex and thus dramatically affected the degradation activities. ZZ151 quickly, specifically, and effectively induced SOS1 degradation; displayed potent antiproliferation activities against a broad panel of KRAS mutant-driven cancer cells; and showed superior anticancer activities in the KRAS G12D -and G12V -mutant xenografts in mice. ZZ151 is a promising lead for developing new chemotherapies targeting KRAS mutants.
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