Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant 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 KRASG12D- and G12V-mutant xenografts
in mice. ZZ151 is a promising lead for developing new chemotherapies
targeting KRAS mutants.